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4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative and preparation method thereof

A technology based on butylcarbamic acid and piperazine, which is applied in the field of pharmaceutical compounds and its preparation, can solve the problem of no strengthening effect or ignition effect of common dopamine receptor agonists or antagonists, reduce behavioral sensitization, and weaken animal conditioned position Preference and other issues, to achieve the effect of stable reaction yield, high affinity, and less environmental pollution

Active Publication Date: 2013-05-01
宁波市微循环与莨菪类药研究所 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Both in vivo and in vitro experiments of BP897 were shown as D 3 Receptor partial agonist, studies have shown that BP897 can inhibit drug reinforcement and reward, weaken animal conditioned place preference, reduce behavioral sensitization, inhibit drug-seeking behavior or drug craving, and there is no common dopamine receptor agonist or antagonist Reinforcement or ignition effect

Method used

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  • 4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative and preparation method thereof
  • 4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative and preparation method thereof
  • 4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Phenylpiperazine hydrochloride (1a)

[0043] 1. In a 100ml three-necked flask equipped with mechanical stirring, reflux condenser, and thermometer, add 8.93g (0.05mol) of di-(β-chloroethyl)amine hydrochloride, 4.65g (0.05mol) of aniline, and 20ml of normal Butanol, potassium carbonate 13.8g (0.10mmol), N 2 Protection, reflux reaction, and TLC to detect the progress of the reaction. After the reaction is completed, filter while it is hot, the filtrate is lowered to room temperature, and solids are precipitated. Add an appropriate amount of methanol to dissolve the solids, and pass through hydrogen chloride gas to make the solution acidic. Then add excess ether to precipitate precipitation, filter with suction, and wash the filter cake with a small amount of ether. The crude product of 1-phenylpiperazine hydrochloride was obtained, which could be directly used in the next reaction, and the pure product could be obtained by recrystallization from absolute ethanol. (U.S. ...

Embodiment 2

[0067] Intermediate p-fluorophenyltrichloromethoxyformate (5a)

[0068] Take 17.78g of triphosgene (0.06mol), dissolve it in 100mL of dichloromethane, put it in a 250mL three-neck flask, and stir it electrically; take another 16.86g (0.15mol) of p-fluorophenol, 16.9mL of triethylamine, dissolve it in 45mL In dichloromethane, slowly add dropwise into the triphosgene solution, after the dropwise addition, stir for 30 minutes, heat to reflux, after TLC monitors the reaction, stop heating, after cooling to room temperature, add 50mL of water, stir for 30 minutes, let stand to separate layer, the organic layer was washed twice with 20 mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to recover the solvent to obtain a white solid, which was weighed dry and weighed 13.38 g, with a yield of 80.5%. (U.S. Diane U3000, HPLC: t R =10.5min, λ=254nm, CH 3 OH:H 2 O=7:3,T f =1.0ml / min, content 98.5%), melting point: 114-118°C. IRυ max (...

Embodiment 3

[0085] Embodiment 3: the preparation of compound 6a

[0086] Step 1: As shown in Step A in Formula II, compound 1a was synthesized according to Example 1;

[0087] Step 2: Synthetic compound 2a (i.e. intermediate 2a, similar below) as shown in step B in formula II. details as follows:

[0088] Add 15.6g (0.079mol) of compound 1a, 426.7g (0.095mol) of compound, 15.7g (0.095mol) of potassium iodide, 21.8g (0.158mol) of potassium carbonate and 500mL of acetonitrile into a 1000mL three-necked flask, mechanically stir and reflux for 4h Afterwards, cool and filter, and the mother liquor stands still for crystallization. After suction filtration, the filter cake was dried to obtain 2a25.8g, with a yield of 90%.

[0089] Step 3: Compound 3a was synthesized as shown in Step C of formula II (ie intermediate 3a, similar to the following). details as follows:

[0090] Dissolve 25.4g (0.070mol) of compound 2a in 500mL of absolute ethanol, put it in a 1000mL three-neck bottle, slowly...

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Abstract

The invention discloses a phenyl piperazidine heterocyclic medicinal compound. The compound has high affinity to a dopamine D3 receptor, so that the compound can be used for treating addiction to and dependence on medicines such as cocaine, and a central nervous system disorder relevant to the addiction and the dependence. The compound is a 4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative with a structural formula as Formula (1) as shown in the specification. A synthetic method of the derivate comprises the steps that substituted aniline and 2-(beta-chloroethyl) amine hydrochloride reacts in a solvent by taking inorganic base as an acid-binding agent to form corresponding substituted phenyl piperazidine hydrochloride 1; substituted phenyl piperazidine hydrochloride 1 and N-(delta-bromobutyl) phthalimide react in acetonitrile by taking K2CO3 as an acid-binding agent and under catalysis of KI to form a reaction intermediate 2; the intermediate 2 is subjected to hydrazinolysis to form an intermediate 3; and the intermediate 3 and an intermediate 5 are condensed by taking triethylamine as an acid-binding agent and a catalyst to form a target product I. The intermediate 5 is obtained in a manner that triphosgene and substituted aromatic phenol conduct partial condensation reaction in methylene chloride.

Description

technical field [0001] The present invention relates to a class of medicinal compounds and a preparation method thereof, in particular to a class of phenylpiperazine heterocyclic compounds. 3 The receptor has a high affinity and can be used for the treatment of drug addiction and dependence on cocaine and other related central nervous system disorders. Background technique [0002] Literature (Science1997, 278: 58-63, Eur J Neurosci2002, 15 (12): 2016-2026, Trends Pharmacol Sci1994, 15: 374-379) and other research results show that D 3 The receptor is closely related to the mesolimbic dopamine pathway, and the increased release of dopamine in the nucleus accumbens putamen in the mesolimbic system is a key site for the euphoric and rewarding effects of addictive drugs. [0003] Literature (Crit Rev Neurobiol1998, 12:37-67, Brain Res Brain Res Rev2000, 31:277-287, Nature1999, 400:371-375, Eur Psychiatry2000, 15:140-146) and other research results believe that dopamine D 3 Pa...

Claims

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Application Information

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IPC IPC(8): C07D295/13A61P25/30A61P25/28
Inventor 周文华李铭东徐泽民余卫国
Owner 宁波市微循环与莨菪类药研究所
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