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Preparation method for varenicline intermediate

A technology of varenicline and intermediates, applied in the directions of oxidation reaction preparation and the like, can solve the problems of low yield, difficult product purification, unsuitable for industrial amplification, etc., and achieves simple synthesis steps, mild reaction conditions, and low production costs. Effect

Inactive Publication Date: 2014-02-12
SHANGHAI SYNCORES TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] In the second step of the method, osmium tetroxide is used as an oxidation reagent. Osmium tetroxide is highly toxic, causing great environmental pollution and high prices.
Due to the limitation of reagents and consideration of the environment, operability and other aspects, the industrialization of this route is limited
[0012] 2) The document Chem.Commun., 1999, 819–820 discloses the following method, using potassium permanganate to oxidize compound I to obtain compound II, but the yield is low (only up to 49%), which is not suitable for industrial scale-up
[0016] In summary, the synthesis method of varenicline intermediate (compound II) disclosed in the existing patent literature generally has high cost, low production efficiency, difficult purification of the product, unfriendly to the environment, and is not suitable for large-scale industrialization Production and other defects

Method used

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  • Preparation method for varenicline intermediate
  • Preparation method for varenicline intermediate
  • Preparation method for varenicline intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Add 50g (352mmol, 1.0eq) of 1,4-dihydro-1,4-methanone, 123.6g (1.05mol, 3.0eq) of N-methyl-N-morpholine oxide, 62mg ( 0.18mmol, 0.05%eq) Potassium osmate dihydrate, 250mL methanol, 250mL water, the system was clear after stirring, and stirred at 20~30°C for 8 hours. HPLC detected that the reaction of the raw materials was complete. The reaction system was concentrated under reduced pressure to evaporate methanol, and water was added to 250 mL. After stirring, the mixture was filtered, and the filter cake was washed with 50 mL of petroleum ether. After the filter cake was dried, 53 g of powdery solid was obtained, which was the varenicline intermediate (compound II), with a melting point of 176-178°C, a content of 98%, a purity of 99.7%, and a yield of 83.8%.

Embodiment 2

[0035] Add 50g (352mmol, 1.0eq) 1,4-dihydro-1,4-methyconaphthalene, 123.6g (1.05mol, 3.0eq) N-methyl-N-morpholine oxide, 62mg ( 0.18mmol, 0.05%eq) Potassium osmate dihydrate, 350mL methanol, 150mL water, the system was clear after stirring, and stirred at 10~20°C for 15 hours. HPLC detected that the reaction of the raw materials was complete. The reaction system was concentrated under reduced pressure to evaporate methanol, and water was added to 250 mL. After stirring, the mixture was filtered, and the filter cake was washed with 50 mL of petroleum ether. After the filter cake was dried, 52 g of powdery solid was obtained, which was the varenicline intermediate (compound II), with a melting point of 176-178°C, a content of 99%, a purity of 99.5%, and a yield of 83.1%.

Embodiment 3

[0037] Add 50g (352mmol, 1.0eq) 1,4-dihydro-1,4-methyconaphthalene, 123.6g (1.05mol, 3.0eq) N-methyl-N-morpholine oxide, 62mg ( 0.18mmol, 0.05%eq) Potassium osmate dihydrate, 50mL methanol, 450mL water, the system was clear after stirring, and stirred at 40~50°C for 30 hours. HPLC detected that the reaction of the raw materials was complete. The reaction system was concentrated under reduced pressure to evaporate methanol, and water was added to 250 mL. After stirring, the mixture was filtered, and the filter cake was washed with 50 mL of petroleum ether. After the filter cake was dried, 46 g of powdery solid was obtained, which was the varenicline intermediate (compound II), with a melting point of 176-178°C, a content of 98%, a purity of 99.0%, and a yield of 72.7%.

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Abstract

The invention relates to a preparation method for a varenicline intermediate. The method includes: subjecting 1, 4-dihydro-1, 4-methanonaphthalene to an oxidation reaction under the action of an oxidizing agent so as to generate the varenicline intermediate. The oxidizing agent is an osmic acid salt or its hydrate, the oxidation reaction undergoes in a solvent in the presence of N-methyl-N-morpholine oxide, and the solvent is a mixed solvent of water and any one or more of the following organic solvents: C1-C6 alcohol solvents, ketone solvents, ether solvents and nitrile solvents. For the mixed solvent, water and the organic solvent are in a volume ratio of 1:0.1-9. The method provided by the invention has the advantages of low production cost, simple operation, mild reaction conditions and environmental friendliness, and can prepare the product that is easy to purify and has purity up to over 99%. With high yield, the method is suitable for both small-scale preparation in laboratories and large-scale industrialized production.

Description

technical field [0001] The present invention relates to a method for preparing a varenicline intermediate, in particular to a method for preparing 1,2,3,4-tetrahydro-1,4-methano-naphthalene-cis-2,3-diol . Background technique [0002] Varenicline is a drug developed by Pfizer of the United States for the treatment of nicotine addiction. Its trade name is Chantix, which was approved for marketing by FDA in the US and EMEA in Europe in May and August 2006 respectively. Varenicline is the first drug to produce smoking cessation effects by affecting the neural mechanism of nicotine dependence, and it is also the first smoking cessation prescription drug approved by the FDA in the past ten years. Its smoking cessation effect is better than that of benzodiazepine-L-tartrate Molecular formula is C 17 h 19 N 3 o 6 , CAS registry number: 375815-87-5). [0003] Varenicline, whose chemical name is 2,3,4,5-tetrahydro-1,5-methylbridge-1H-3-benzazepine, has the following structural...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C35/37C07C29/48
CPCC07C29/48
Inventor 张席妮廖文静黄鲁宁
Owner SHANGHAI SYNCORES TECH INC
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