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Preparation method of (R)-3-(3-methoxy phenyl)-N,N,2-trimethylpent-3-ene-1-amine

A technology of methoxyphenyl and trimethylpentane, applied in the field of drug synthesis, can solve the problems of cumbersome operation, many steps, and inability to obtain high optical purity, achieve mild reaction conditions, short synthesis route, and avoid reagents and solvents Effect

Active Publication Date: 2012-01-18
NHWA PHARMA CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The currently disclosed method for preparing the compound of formula II has many steps and complicated operations, and cannot obtain tapentadol with high optical purity.

Method used

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  • Preparation method of (R)-3-(3-methoxy phenyl)-N,N,2-trimethylpent-3-ene-1-amine
  • Preparation method of (R)-3-(3-methoxy phenyl)-N,N,2-trimethylpent-3-ene-1-amine
  • Preparation method of (R)-3-(3-methoxy phenyl)-N,N,2-trimethylpent-3-ene-1-amine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1, 3-dimethylamino-1-(3-methoxyphenyl)-2-methyl-1-propanone (compound A)

[0035]

[0036] N, N, N', N'-tetramethylmethylenediamine (46.3g, 0.45mol) was added into methyl tert-butyl ether (100ml), and acetyl chloride (37.0g, 0.47mol) was added dropwise under ice-cooling A solution of methyl tert-butyl ether (100ml) was stirred at room temperature for 1h, and the solvent was removed under reduced pressure. Add isopropanol (150ml) to dissolve the residue, continue to add 1-(3-methoxyphenyl)-1-propanone (50.9g, 0.31mol), heat up to reflux under stirring, react for 5h, cool to room temperature, Add water and toluene. The organic layer was discarded, 30% NaOH aqueous solution (50 ml) was added to the aqueous phase, stirred for 10 minutes, 200 ml of ethyl acetate was added, and the layers were separated. The organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give oily 3-dimethylamino-1-(3-methoxyphenyl)-2-...

Embodiment 2

[0037] Example 2, (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (I)

[0038]

[0039]Add L-(-)-dibenzoyl tartaric acid monohydrate (111.7g, 0.29mol) into 30ml of methanol and 180ml of acetone, stir to dissolve, then add compound A (64.0g, 0.29mol), at 38°C Stir for 48h, cool to room temperature, precipitate a large amount of white solid salt, filter with suction, wash the filter cake with acetone, and obtain 126.0g (S)-3-(dimethylamino)-1-(3-substituted oxybenzene) after drying Base)-2-methylpropan-1-one·L-(-)-dibenzoyl tartrate, the yield was 75%.

[0040] The above white solid was added to 500ml of methyl tert-butyl ether, 67ml of diethylamine was added under stirring at room temperature, and stirring was continued for 1h. Concentrate to dryness by suction filtration to obtain 45.5g light yellow oil, compound of formula I, its MS-ESI (m / z): 222 (M+1); 1 H-NMR (400MHz, CDCl 3 )δ: 7.56(d, J=8.0Hz, 1H), 7.52(s, 1H), 7.38(t, J=8.0Hz, 1H), 7.10(d, J=8.0...

Embodiment 3

[0041] Example 3, (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine (II)

[0042]

[0043] At room temperature, ethyltriphenylphosphine bromide (26.7g, 72mmol) was added to methyl tert-butyl ether (150ml), potassium tert-butoxide (8.1g, 72mmol) was added under stirring, and stirring was continued for 1h. After cooling in an ice bath to below 20°C, a solution of I (13.3g, 60mmol) in methyl tert-butyl ether (50ml) was added dropwise. After stirring at room temperature for 2 hours, cool down in an ice bath, slowly add 100ml of water, separate the liquids, concentrate the organic phase, then extract with petroleum ether, wash with water, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 13.5g of the crude compound of formula II in the form of light yellow oil .

[0044] The crude compound of formula II above was dissolved in 200ml of ethyl acetate, and 12ml of ethyl acetate solution of hydrogen chloride with a concentration of 6mol / L was added dropwis...

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Abstract

The invention belongs to the technical field of drug synthesis, and discloses a preparation method of (R)-3-(3-methoxy phenyl)-N,N,2-trimethylpent-3-ene-1-amine. The preparation method comprises the following step of: carrying out wittig reaction or Horner-Emmons-Wittig reaction on an alkaline substance and a compound shown in formula I at a certain temperature in an inert solvent under alkaline conditions to obtain a compound shown in formula II; or further preparing the compound shown in the formula II into a salt. The preparation method has the advantages of short synthesis route, mild reaction conditions in each step and no need for special equipment, is simple to operate, and is suitable for industrial production; the product is easy to separate and purify; and by using the synthesis method, a high-purity finished product can be obtained, and strong-toxicity reagents and solvents are not used.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis and relates to the preparation of tapentadol intermediate (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine Preparation. Background technique [0002] Tapentadol (Tapentadol), chemical name 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride, was produced by Gruenenthal, Germany The central nervous system analgesic created by the company has dual effects of opioid μ receptor agonism and norepinephrine reabsorption inhibition. In November 2008, the US FDA approved its immediate-release tablet for marketing, and it is clinically used to relieve central nervous system pain in adults. to severe acute pain. This compound has the following structure: [0003] [0004] According to literature reports, the synthetic routes mainly contain the following: [0005] 1. The patent EP0693475 firstly reported the synthesis of tapentadol. Using 1-(dimethylami...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/62C07C213/08
Inventor 马彦琴赵士魁杨相平杨蕊彭卫娟
Owner NHWA PHARMA CORPORATION
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