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N-(naphthoxyalkyl)heteroarylpiperidine compounds and preparation method and applications thereof

A compound, piperidine technology, applied in the field of drug synthesis, can solve the problem of single action site of antipsychotic drugs, and achieve the effect of easy-to-obtain raw materials, mild reaction conditions, and simple operation

Active Publication Date: 2015-05-27
ZHEJIANG HUAHAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In view of this, the object of the present invention is to provide a kind of N-(naphthyloxyalkyl) heteroaryl piperidine compound with multiple action targets for the defect of single action site of antipsychotic drugs in existing clinical application

Method used

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  • N-(naphthoxyalkyl)heteroarylpiperidine compounds and preparation method and applications thereof
  • N-(naphthoxyalkyl)heteroarylpiperidine compounds and preparation method and applications thereof
  • N-(naphthoxyalkyl)heteroarylpiperidine compounds and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: N-(2-(7-(3-(4-(6-fluorobenzisoxazol-3-yl)piperidin-1-yl)propoxy)naphthalene-1-yl)ethyl base) the preparation of acetamide

[0046] 1. Preparation of N-(2-(7-(3-chloropropoxy)naphthalene-1-yl)ethyl)acetamide

[0047] Add N-(2-(7-methoxynaphthalen-1-yl)ethyl)acetamide 6g (24.6mmol) and 24ml (6N) concentrated hydrochloric acid at room temperature and heat to reflux at 100°C for 9h. After the reaction was detected by TLC (acetone:n-hexane=1:1), cooling and crystallization was carried out. The solid was obtained by filtration and chromatographed on a silica gel column (eluent: acetone:n-hexane=1:1) to obtain 1.4 g of white N-(2-(7-hydroxynaphthalen-1-yl)ethyl)acetamide solid.

[0048] At room temperature, in a 50ml three-necked flask, add 1.4g (6.1mmol) N-(2-(7-hydroxynaphthalene-1-yl)ethyl)acetamide, 2.5g (18.3mmol) of potassium carbonate, 1.9g (12.2mmol) 1-bromo-3-chloropropane and acetone 15ml, reflux at 60°C, stir for 6h, TLC (acetone:n-hexane=1:1) detects ...

Embodiment 2

[0051] Example 2: Acetic acid-O-(2-(7-(3-(4-(6-fluorobenzisoxazol-3-yl)piperidin-1-yl)propoxy)naphthalene-1-yl ) Preparation of ethyl) ethyl ester

[0052] 1. Preparation of acetic acid-2-(7-(3-chloropropoxy)naphthalene-1-yl)ethyl ester

[0053] Add 6 g (24.7 mmol) of acetic acid-2-(7-methoxynaphthalen-1-yl) acetate and 24 ml (6N) concentrated hydrochloric acid at room temperature and heat to reflux at 100° C. for 9 h. After the reaction was detected by TLC (acetone:n-hexane=1:1), cooling and crystallization was carried out. The obtained solid was filtered and chromatographed on a silica gel column (eluent: acetone:n-hexane=1:1) to obtain 1.3 g of white 2-(7-hydroxynaphthalen-1-yl)ethyl)ethyl acetate as a solid.

[0054] At room temperature, in a 50ml three-necked flask, 1.3g (5.7mmol) acetic acid-2-(7-hydroxynaphthalene-1-yl) ethyl) ethyl ester, 2.4g (17.1mmol) of potassium carbonate, 1.8g ( 11.4mmol) 1-bromo-3-chloropropane and 15ml acetone, reflux at 60°C and stir for 6h...

Embodiment 3

[0057] Example 3S-(2-(7-(3-(4-(6-fluorobenzisoxazol-3-yl)piperidin-1-yl)propoxy)naphthalene-1-yl)ethyl) Preparation of thiol acetate

[0058] 1. Preparation of S-(2-(7-(3-chloropropoxy)naphthalene-1-yl)ethyl)thiol acetate

[0059] Add S-(2-(7-methoxynaphthalen-1-yl)ethyl)thiol acetate 6g (23.1mmol) and 24ml (6N) concentrated hydrochloric acid at room temperature and heat to reflux at 100°C for 9h. After the reaction was detected by TLC (acetone:n-hexane=1:1), cooling and crystallization was carried out. The solid was obtained by filtration and passed through a silica gel column (eluent: acetone:n-hexane=1:1) to obtain 1.4 g of white S-(2-(7-hydroxynaphthalen-1-yl)ethyl)thiol acetate solid.

[0060] At room temperature, in a 50ml three-necked flask, add 1.4g (5.7mmol) S-(2-(7-hydroxynaphthalene-1-yl) ethyl) mercaptan acetate, potassium carbonate 2.4g (17.1mmol) successively , 1.8g (11.4mmol) of 1-bromo-3-chloropropane and 15ml of acetone, reflux at 60°C and stir for 6h. Aft...

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Abstract

The invention relates to the pharmaceutical synthesis field and discloses N-(naphthoxyalkyl)heteroarylpiperidine compounds and a preparation method and applications thereof. The compounds disclosed by the invention are the compound shown in the formula I and pharmaceutically acceptable acid addition salts thereof, wherein n is 0, 1, 2 or 3; R is acetamino, acetoxy, acethythio, oximido, amino, aminocarbonyl, dimethylamino, diethylamino, hydroxyl, trifluoromethyl, trifluoroacetyl, cyano, phenyl, aldehyde group, benzoyl, fluorine, chlorine, bromine or iodine. The preparation method is as follows: 7-methoxynaphthalene compound used as raw material and 6-fluoro-3-(4-piperidyl)-1,2-benzoisoxazole are used to perform N-alkylation reaction. The N-(naphthoxyalkyl)heteroarylpiperidine compounds can act on 5-HT2A receptor, dopamine D2 receptor and melatonin receptor, are the compounds with the multi-target function and have the antipsychotic function.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to an N-(naphthyloxyalkyl)heteroarylpiperidine compound and its preparation method and application. Background technique [0002] Psychosis is due to the disorder of human thalamus and brain function, which leads to abnormalities in perception, thinking, emotion and behavior of patients. Mental illness usually occurs in young adults, some intermittently, some continue to progress, and gradually tend to become chronic, with high relapse rate and high disability rate. If not actively treated, mental decline and personality changes may occur, and they cannot adapt to society. It is difficult to fulfill the responsibilities to the family and society. With the continuous development of society, the pressure of work and life is increasing, and the number of mentally ill patients is increasing year by year. At present, there are 100 million mentally ill patients in my country, and the mental...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/04A61K31/454A61P25/18
Inventor 隋强顾维钧时慧麟
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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