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Resolution of 1-(4-methoxybenzyl)-octahydro-isoquinoline

A technology of methoxybenzyl and methoxy, which is applied in the field of resolution of 1--octahydro-isoquinoline, and can solve problems such as similar efforts of octabasic analogues that have not been reported

Inactive Publication Date: 2013-09-25
DIVI S LAB LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, they did not report similar efforts using octamer analogs

Method used

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  • Resolution of 1-(4-methoxybenzyl)-octahydro-isoquinoline
  • Resolution of 1-(4-methoxybenzyl)-octahydro-isoquinoline

Examples

Experimental program
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Embodiment 1

[0030] Example 1: Resolution of (±)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isoquinoline:

[0031] Solid R-naproxen (36.4 g, 0.157 moles) was added to a solution of racemic octabasic (50.0 g, 0.1942 moles) in 300 ml of toluene. The reaction mixture was heated to 45-55 °C and then stirred at the same temperature for 1 h. The monolith was allowed to cool to 25-35°C for about 30 minutes, further cooled to 6-14°C and aged at the same temperature for 2h. The (-) octabasic-R-naproxen salt thus formed was filtered at 6-14°C and the wet cake was washed with 30 ml of toluene. It was then purified by slurrying in toluene at 40-50 °C for about 1 h, cooled to 25-35 °C, then further cooled to 6-14 °C, stirred for 2 h, filtered and washed with toluene (4.5 ml) and dried to give crystalline (-) octabasic-R-naproxen salt (32.0 g, 33.8% yield) having an optical rotation of (-) 70 to 75° at 20°C, 589 nm, in 1% methanol. The mother liquor containing the undesired enantiomer (+ octabasic...

Embodiment 2

[0032] Example 2: Resolution of (±)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isoquinoline:

[0033] The racemic octabasic HBr salt (131.5 g) was added to a flask containing 500 ml of water, cooled to 10-15 °C, the pH was adjusted to 12 to 13 using sodium hydroxide lye and 325 ml of toluene was added to extract The free racemic octabasic compound released. The toluene layer was washed with water and the organic layer was dried. The toluene layer containing 100.0 g (0.388 moles) of free octabasic was charged to a flask and 200 ml of toluene was added. Solid R-naproxen (72.8 g, 0.316 moles, rotation about -40°) was added to the solution. The reaction mixture was heated to 45-55 °C, stirred for 1 h, then cooled to 25-35 °C, maintained for about 30 min, further cooled to 6-14 °C and maintained at the same temperature for 2 h. The (-) octabasic-R-naproxen salt thus formed was filtered at 6-14°C and the wet cake was washed with 60 ml of toluene. The mother liquors were colle...

Embodiment 3

[0035] Example 3: Decomposition of (±)-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isoquinoline:

[0036] The toluene layer containing about 100 g (0.388 moles) of the racemic octabasic compound as in Example 2 above was concentrated under vacuum below 50 °C to remove the toluene to give the crude racemic octabasic group. To this was added enough ethyl acetate to bring the total volume to 400ml. To this solution was added solid R-naproxen (72.8 g, 0.316 mol, optical rotation about -40°). The reaction mixture was heated to 45-55 °C, stirred for 1 h, then cooled to 25-35 °C, maintained for about 30 min, further cooled to 6-14 °C and maintained at the same temperature for 2 h. The (-) octabasic-R-naproxen salt thus formed was filtered at 6-14°C and the wet cake was washed with 60 ml of ethyl acetate. The mother liquors were collected separately for recovery of R-naproxen, DL-octabasic and (+)-octabasic.

[0037] The (-) octabasic-naproxen salt was slurried in ethyl acetate a...

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Abstract

The invention provides a resolution method of racemic 1-(4-methoxybenzyl)-octahydro-isoquinoline by (R)-2-(6-methoxy-2- naphthyl) propionic acid with good yield, wherein the racemic 1-(4-methoxybenzyl)-octahydro-isoquinoline is a key intermediate for synthetizing a cough-relieving medicine dextromethorphan. A resolving agent and unneeded isomers of octahydro-isoquinoline can well be recovered.

Description

technical field [0001] The present invention relates to the resolution of 1-(4-methoxybenzyl)-octahydro-isoquinoline. [0002] Introduction [0003] A number of analogs of morphine have been prepared and tested for different activities, in particular in order to achieve the isolation of several activities of morphine and to enhance or inhibit selected activities. In this regard, the contribution of the groups of Hellerbach and Schnider to the development of morphinans as useful antitussive and antirheumatic analgesics should be considered outstanding (between 1949 and 1962, in Helv. Chim. Acta. series of publications). In particular the 3-oxo-N-alkylmorphinans have gained prominence in medicine. Morphinans are prepared from isoquinoline-type starting materials by cyclization. First they prepared the equally useful racemic form of 3-oxo-N-alkylmorphinans. However, it was quickly established qualitatively and quantitatively that the L- and D-isomers differ in their actions....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20
Inventor 穆拉利·克里希纳·普拉萨德·迪维潘德亚拉·斯里尼瓦·拉奥拉武·文卡塔·拉玛纳
Owner DIVI S LAB LTD
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