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Synthesis methods of methyl esters of 1-amino-cycloheptane-carboxylic acid

A technology for methyl phenylcycloheptanecarboxylate and phenylcycloheptanecarboxylic acid, which is applied in the field of synthesis of 1-phenylcycloheptanecarboxylic acid and its esters, and can solve the problem of cumbersome operations, long and shortened synthetic routes Reaction routes and other issues to achieve the effects of simplifying reaction operations, shortening reaction steps, saving energy and environmental protection

Inactive Publication Date: 2015-11-11
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The currently reported synthetic route is relatively long, and the operation is cumbersome. The shortened reaction route makes the reaction easy to operate, which is conducive to saving resources and environmental protection.

Method used

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  • Synthesis methods of methyl esters of 1-amino-cycloheptane-carboxylic acid
  • Synthesis methods of methyl esters of 1-amino-cycloheptane-carboxylic acid
  • Synthesis methods of methyl esters of 1-amino-cycloheptane-carboxylic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Add 47.86g (0.30mol) of t-BuOK to a 500mL three-necked flask, a small amount of KI, stir with 100mL of DMF, control the temperature in an ice-salt bath below 0°C, and dropwise add [10.00g (0.085mol) of phenylacetonitrile plus DMF50mL] mixed solution, Keep the temperature below 0°C, drop it for 30 minutes, stir for 30 minutes, add 20.57g (0.085mol) of 1,6-dibromohexane in 50mL DMF mixed solution dropwise, keep the temperature below 0°C, raise the temperature to 80°C, and react for 4h Afterwards, TLC detected that the reaction was complete, the reaction solution was poured into cold water, extracted 3 times with EA, the organic layers were combined, washed once with water, washed once with saturated NaCl solution, and washed once with anhydrous NaCl solution. 2 SO 4 Dry, filter and concentrate the next day. 1 H-NMR (400MHz, CDCl 3 )δ: 7.36~7.26(m,5H), 1.89~1.83(m,2H), 1.79~1.73(m,2H), 1.34~0.99(m,8H).

[0029] Add 85.6 mL of ethylene glycol and 24.08 g (0.43 mol) of KO...

Embodiment 2

[0032] Add t-BuOK33.60g (0.30mol) and a small amount of KI to a 500mL three-necked flask, stir in 100mL of DMF, control the temperature in an ice-salt bath below 0°C, add dropwise a 50mL DMF solution of 8.99g (0.06mol) of methyl phenylacetate, and keep When the temperature is below 0°C, after 30 minutes of dripping, after stirring for 30 minutes, add 1,6-dibromohexane 13.50g (0.06mol) in 50mL of DMF dropwise, keep the temperature below 0°C, raise the temperature to 80°C, and react for 4 hours, TLC detected that the reaction was complete, the reaction solution was poured into cold water, extracted 3 times with EA, combined the organic layers, washed once with water, washed once with saturated NaCl solution, and washed once with anhydrous NaCl solution. 2 SO 4 Dry, filter and concentrate. Purification by column chromatography was eluted with petroleum ether to obtain the product. Yield 88.6%, HPLC purity 98.6%.

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Abstract

The invention discloses 1-amino-cycloheptane-carboxylic acid and two synthesis methods of esters of 1-amino-cycloheptane-carboxylic acid. One synthesis method comprises the following steps: conducting cyclization on benzyl cyanide and 1,6-dibromohexane (1,6-dichlorohexane or 1,6-diiodohexane) under the condition that a strong alkali exists and potassium iodide (or sodium iodide) is taken as a catalyst, and conducting hydrolysis on the cyclization product under the action of an acid or an alkali, and carrying out a reaction between the hydrolysis product and methanol under the action of catalysis, so as to obtain one target product; the other synthesis method comprises the following steps: conducting cyclization on methyl phenylacetate and 1,6-dibromohexane (1,6-dichlorohexane or 1,6-diiodohexane) under the condition that a strong alkali exists and potassium iodide (or sodium iodide) is taken as a catalyst. The synthesis methods of the methyl esters of 1-amino-cycloheptane-carboxylic acid have very outstanding advantages that the reaction is simple and convenient; the reaction steps are greatly shortened; the functions of economization and environmental protection are further achieved.

Description

technical field [0001] The invention relates to the production field of pharmaceutical intermediates, in particular to a synthesis method of 1-phenylcycloheptane carboxylic acid and its ester (methyl ester). Background technique [0002] 1-Phenylcycloheptane carboxylic acid and its esters (methyl ester, ethyl ester, etc.) are important intermediates of muscarinic M3 receptor antagonist quinucidine derivatives (such as AZD8683). At present, the synthetic steps of methyl 1-phenylcycloheptanecarboxylate are many, and the operation is loaded down with trivial details, and the simple reaction formula is as follows: [0003] [0004] The currently reported synthesis route is relatively long, and the operation is cumbersome, and the reaction route is shortened, which makes the reaction operation simple and convenient, which is beneficial to resource saving and environmental protection. Contents of the invention [0005] The purpose of the present invention is to provide two k...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/08C07C67/343C07C69/753
CPCC07C67/08C07C51/08C07C67/343C07C253/30
Inventor 陈国良吴春福邢磊周林波王立辉杨静玉鲁萌萌
Owner SHENYANG PHARMA UNIVERSITY
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