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Method for preparing tapentadolhydrochloride and intermediate thereof

A technology of racemate and enantiomer, applied in the field of medicinal chemistry, to achieve the effect of sufficient market supply and low price

Inactive Publication Date: 2011-04-06
TOPHARMAN SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this reaction has never been applied to the preparation of tapentadol nuclei

Method used

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  • Method for preparing tapentadolhydrochloride and intermediate thereof
  • Method for preparing tapentadolhydrochloride and intermediate thereof
  • Method for preparing tapentadolhydrochloride and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057]

[0058] Put 30ml N,N-dimethylformamide, 3-tert-butyldimethylsiloxybenzaldehyde 14.2g (0.06mol, 1eq), and R-proline 2.07g (0.018mol) into a 100ml single-necked flask. , 0.3eq), slowly drip 8.8ml (0.12mol, 2eq) of propionaldehyde in an ice-water bath. After reacting for about 3h, add 30ml of water to stop the reaction; then add appropriate amount of ethyl acetate for extraction, dry, and spin to dry to obtain an oil (2R,3S)-3-hydroxy-2-methyl-3-(3-tert-butyldimethylsiloxyphenyl)propanal, the oily substance is directly put into the next reaction.

Embodiment 2

[0060]

[0061] Put 20ml of dichloromethane and 3.59g (0.044mol, 1.1eq) of dimethylamine hydrochloride into a 250ml single-necked flask. Slowly add 4.45g (0.044mol, 1.1eq) of triethylamine under ice water bath, and react for a while Then add the above-mentioned preparation oil (2R, 3S)-3-hydroxy-2-methyl-3-(3-tert-butyldimethylsiloxyphenyl)propanal (0.04mol, 1.0eq) in methanol 50ml, add NaBH4 in batches, and react at low temperature for 2h; then, add appropriate amount of water and ethyl acetate for extraction, dry, and spin dry to obtain an oily (1S, 2S)-3-(dimethylamino)-2 -Methyl-1-(3-tert-butyldimethylsiloxyphenyl)-1-propanol, the oily substance is directly put into the next reaction.

Embodiment 3

[0063]

[0064] In an ice-water bath, add the oily (1S, 2S)-3-(dimethylamino)-2-methyl-1-(3-tert-butyldimethylsiloxybenzene) prepared in Example 2 above. Yl)-1-propanol, put 50ml of dichloromethane, 9.144g (0.048mol, 1.2eq) of p-toluenesulfonyl chloride, 6.06g (0.06mol, 1.5eq) of triethylamine, a small amount of 4-dimethylaminopyridine into The reaction takes about 3 hours; then, add appropriate amount of water to terminate the reaction, extract with ethyl acetate, dry, and spin to dry, to obtain a white solid (1S, 2S)-3-(dimethylamino)-2-methyl-1-( 3-tert-Butyldimethylsiloxyphenyl)propyl-4-toluenesulfonate, the two-step yield is 85%.

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Abstract

The invention relates to a method for preparing a tapentadolhydrochloride and an intermediate thereof, in particular to a compound shown in a structural formula II, an enantiomer, a diastereoisomer and a raceme of the compound, a mixture of the enantiomer and the diastereoisomer and salts thereof, a method for preparing a compound shown in the formula II, application of the compound shown in the formula II in preparation of the tapentadolhydrochloride, and an intermediate for preparing the compound shown in the formula II. The method for preparing the tapentadolhydrochloride has the advantages of mild condition, simplicity of operation, high stereoselectivity, security, environment friendliness, suitability for large-scale commercial production, and abundant and low-cost raw material and catalyst.

Description

Technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a preparation method of tapentadol and its intermediates. More specifically, it relates to compounds of the following formula II and their enantiomers, diastereomers, racemates, enantiomers or diastereomer mixtures and their mixtures The salt, its preparation method and the method for preparing tapentadol using the compound of formula II, in addition, the present invention also relates to the intermediate for preparing the compound of formula II. Background technique [0002] [0003] Tapentadol hydrochloride (Tapentadol) structure [0004] Tapentadol hydrochloride (Tapentadol, structural formula as shown above), chemical name is 3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloric acid salt. Tapentadol hydrochloride is a dual-effect analgesic jointly developed by Grunenthal GmbH and Johnson & Johnson. It is a mu-type opioid receptor agonist and norepinephrine rea...

Claims

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Application Information

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IPC IPC(8): C07F7/18C07C215/54C07C213/00C07C205/44C07C201/12C07C309/73C07C303/28C07C211/29C07C209/68C07C211/49C07C209/36
CPCC07C213/08C07C217/72
Inventor 孙占奎柳永建李海泓
Owner TOPHARMAN SHANGHAI
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