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Method for synthesizing Varenicline intermediate 2, 3, 4, 5-tetralin-1, 5-methylene-hydrogen-benzoazepine

An intermediate, methylene technology, applied in the field of synthesis of organic intermediates, can solve the problems of difficult separation, environmental pollution, high cost, etc., and achieve the effects of simple production process, simplified method, and reduced cost of raw materials

Inactive Publication Date: 2010-04-14
上海立科化学科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

One of the routes uses the expensive and highly toxic OsO 4 ; Route two uses dangerous and flammable butyllithium, and also uses potassium dichromate, which produces a large amount of chromium sludge, which is not only difficult to separate but also may cause serious environmental pollution; A large amount of noble metal catalyst is used, and the control of reaction conditions is very strict

Method used

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  • Method for synthesizing Varenicline intermediate 2, 3, 4, 5-tetralin-1, 5-methylene-hydrogen-benzoazepine
  • Method for synthesizing Varenicline intermediate 2, 3, 4, 5-tetralin-1, 5-methylene-hydrogen-benzoazepine
  • Method for synthesizing Varenicline intermediate 2, 3, 4, 5-tetralin-1, 5-methylene-hydrogen-benzoazepine

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Embodiment 1

[0039] A method for synthesizing varenicline M intermediate 2,3,4,5-tetrahydro-1,5-methylene-hydrogen-benzazepine, comprising the steps of:

[0040] The first step: take a 2L four-necked bottle (mechanical stirring, thermometer, constant pressure dropping funnel), add 137g (1 mole) anthranilic acid, 2.4g (0.015 mole) trichloroacetic acid, 1L tetrahydrofuran (THF) solvent, Place it in an ice-salt bath, add 192g (1.64 moles) of isoamyl nitrite dropwise under stirring, and drop it in about 10 minutes. After dropping, remove the ice-water bath, place the reaction bottle at room temperature, and continue to stir for 2 h. Cool the reaction solution to about 0°C with an ice-water bath, filter under reduced pressure to obtain the diazonium salt filter residue, wash it with cold THF until the wash solution becomes colorless, and then wash it with 1L of cold CH 2 Cl 2rinse. Carefully transfer the wet diazonium salt slurry to a 1L four-neck flask (with mechanical stirring, reflux cond...

Embodiment 2

[0047] The first step: take a 2L four-necked bottle (mechanical stirring, thermometer, constant pressure dropping funnel), add 137g anthranilic acid, 2.4g trichloroacetic acid, 1L Me-THF solvent, place in an ice-salt bath, stir 192g of isoamyl nitrite was added dropwise, and the drop was completed in about 10 minutes. After dropping, remove the ice-water bath, place the reaction bottle at room temperature, and continue stirring for 2 hours at a temperature of 18-20°C. The reaction solution was cooled to about 0°C with an ice-water bath. Filtrate under reduced pressure, wash the filter residue with cold Me-THF until the wash solution becomes colorless, then wash with 1L cold CH 2 Cl 2 rinse. Carefully transfer the wet slurry to a 1L four-neck flask (with mechanical stirring, reflux condenser, thermometer), add 2.5L CH 2 Cl 2 , 99g of newly prepared cyclopentadiene, stirred at 39.5°C for about 1.5h, stopped the reaction, concentrated to remove the solvent, and then changed ...

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Abstract

The invention relates to a method for synthesizing Varenicline intermediate 2, 3, 4, 5-tetralin-1, 5-methylene-hydrogen-benzoazepine. The method includes the following steps: under the action of catalyst, mixing amyl nitrite with o-aminobenzoic acid solution to generate diazonium salt, then mixing the diazonium salt with cyclopentadiene, and heating to react to generate compound 1; feeding ozone into the solution of compound 1, after complete conversion, adding reducing agent to generate compound 2, then dripping the compound 2 to the mixed solution of triacetoxy sodium borohydride and benzylamine to generate compound 3 by loop closing; and hydrogenating the compound 3 under the action of palladium and carbon for debenzylation and reduction to obtain M intermediate 2, 3, 4, 5-tetralin-1, 5-methylene-hydrogen-benzoazepine. The method has the advantages of greatly simplifying the method for preparing Varenicline intermediate, being simple in production process and safe in operation, well ensuring no harm to the environment and control on production cost, increasing yield and being capable of becoming a process in great industrial production.

Description

technical field [0001] The present invention relates to the synthesis of organic intermediates, in particular to a method for synthesizing varenicline intermediate 2,3,4,5-tetrahydro-1,5-methylene-hydrogen-benzazepine. Background technique [0002] Varenicline tartrate (varenicline t-trate) is a drug developed by Pfizer of the United States for the treatment of nicotine addiction. Its trade name is Chantix, which was approved by the US FDA and the European EMEA in May and August 2006. [0003] Varenicline is a new chemical entity compound, chemical name: 7,8,9,10-tetrahydro-6H-6,10-methylenepyrazinyl[2,3-h][3]benzeneazepam Zazo-L-tartrate; [0004] English name: [0005] 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h][3]benzozepine L-tartrate; [0006] The molecular formula is: C17H19N306; [0007] The relative molecular mass is 361.3; [0008] The CAS registry number is 375815-87-5. [0009] Varenicline binds highly selectively to the α4β2 subtype of neuronal nico...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08
Inventor 陈清泉汤漾凃明
Owner 上海立科化学科技有限公司
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