Method for preparing (S)-1-(4-methoxy benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline

A technology of methoxybenzyl and octahydroisoquinoline, applied in the directions of organic chemistry, organic chemistry, etc., can solve the problems of harsh reaction conditions, waste of raw materials, expensive catalysts, etc., and achieve the effect of cheap raw materials

Inactive Publication Date: 2018-08-10
启东东岳药业有限公司 +1
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

The biggest problem with this method is that the yield can only be close to 50%, resulting in a large amount of waste of raw materials
In addition, there is also a method of introducing (S)-O-tert-butylvalinol group on the nitrogen atom of octahydroisoquinoline, and then performing asymmetric benzylation under the action of butyllithium, and using chiral Ruthenium catalyst carries out the method for asymmetric hydrogenation reduction to synthesize (S)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline, However, due to harsh reaction conditions or expensive catalysts, it is only limited to laboratory synthesis

Method used

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  • Method for preparing (S)-1-(4-methoxy benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Example 1: 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline (1.28g, 5mmol), (R)- N-(5-fluoro-2-hydroxybenzyl)-2-methylpropane-2-sulfinamide (0.13g, 0.5mmol) and 20mL redistilled dichloromethane, cooled to -20°C under nitrogen protection and stirred . Then trichlorosilane (1.35g, 10mmol) was slowly added dropwise into the reaction solution, keeping the temperature in the range of -20 to -15°C, the drop was completed in 0.5 hours, and the temperature was kept at -15°C to continue stirring the reaction. After 12h, slowly add saturated sodium bicarbonate solution until no bubbles are generated, continue stirring for 0.5h and then filter. After the filtrate was separated, the aqueous phase was extracted twice with 20 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was subjected to silica gel column chromatography to obtain 1.15 g of yellow oil, with a yie...

Embodiment 2

[0015] Example 2: 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline (1.28g, 5mmol), (R)- N-(5-fluoro-2-hydroxybenzyl)-2-methylpropane-2-sulfinamide (0.25 g, 1 mmol) and 20 mL redistilled dichloromethane were stirred at -20°C under nitrogen protection. Then trichlorosilane (1.35g, 10mmol) was slowly added dropwise into the reaction solution, keeping the temperature in the range of -20 to -15°C, the drop was completed in 0.5 hours, and the temperature was kept at -15°C to continue stirring the reaction. After 12h, slowly add saturated sodium bicarbonate solution until no bubbles are generated, continue stirring for 0.5h and then filter. After the filtrate was separated, the aqueous phase was extracted twice with 20 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. After using silica gel to pass through the column, 1.12 g of yellow oil was obtained, with a yield of 86.8% and an ee...

Embodiment 3

[0017] Example 3: 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline (1.28g, 5mmol), (R)- N-(5-fluoro-2-hydroxybenzyl)-2-methylpropane-2-sulfinamide (0.50 g, 2 mmol) and 20 mL redistilled dichloromethane were stirred at -20°C under nitrogen protection. Then trichlorosilane (1.35g, 10mmol) was slowly added dropwise into the reaction solution, keeping the temperature in the range of -20 to -15°C, the drop was completed in 0.5 hours, and the temperature was kept at -15°C to continue stirring the reaction. After 12h, slowly add saturated sodium bicarbonate solution until no bubbles are generated, continue stirring for 0.5h and then filter. After the filtrate was separated, the aqueous phase was extracted twice with 20 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was subjected to silica gel column chromatography to obtain 1.14 g of a yellow oil, with a yield of ...

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Abstract

The invention discloses a method for preparing (S)-1-(4-methoxy benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline which is a dextromethorphan intermediate. The method includes selectively hydrogenating 1-(4-methoxy benzyl)-3, 4, 5, 6, 7, 8-octahydro isoquinoline (II) under the condition of (R)-N-(5-fluorine-2-hydroxyl benzyl)-2-methylpropane-2-sulfinamide and trichlorosilane to obtain the (S)-1-(4-methoxy benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline (I). The 1-(4-methoxy benzyl)-3, 4, 5, 6, 7, 8-octahydro isoquinoline (II) is used as a raw material, and the (R)-N-(5-fluorine-2-hydroxyl benzyl)-2-methylpropane-2-sulfinamide is used as an organic chiral ligand. The method has the advantages that the organic chiral ligand is used, and the raw material is inexpensive, safe, simpleand easily available; the reaction temperatures range from -20 DEG C to -15 DEG C, and accordingly the method can be implemented in industrial production; an ee (enantiomeric excess) value of the (S)-1-(4-methoxy benzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline which is a product can reach 63%.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to (S)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8- the key intermediate of dextromethorphan The synthetic method of octahydroisoquinoline. Background technique [0002] (S)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (I) is a synthetic central antitussive drug dextromethorphan key intermediates. This drug has the characteristics of high efficiency, safety, good tolerance, and low addiction, and is an antitussive drug suitable for long-term use or high-dose use. Therefore, the improvement of (S)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline synthesis process will reduce the production of dextromethorphan Cost is of great importance. [0003] The traditional synthesis process of (S)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline uses R-mandelic acid for chiral resolution A method for obtaining a single optically active product. The bigge...

Claims

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Application Information

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IPC IPC(8): C07D217/20
CPCC07D217/20C07B2200/07
Inventor 王巧纯化浩杰高彰运蔡畅龙中柱蔡水洪
Owner 启东东岳药业有限公司
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