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Method for asymmetrical hydrogen transfer of alpha-imino keton for synthesizing chiral salbutamol

A technology for salbutamol and iminone, which is applied in the field of synthesis of chiral-beta amino alcohol compounds and achieves the effects of mild reaction conditions, simple processing and simple post-processing

Inactive Publication Date: 2006-12-20
EAST CHINA NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The catalyst has been successfully used in the asymmetric hydrogen transfer reaction of aromatic ketones, substituted aromatic ketones, α, β-ynones, α-diketones, and imines, but not for the asymmetric hydrogen transfer reactions of α-iminones. Literature report

Method used

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  • Method for asymmetrical hydrogen transfer of alpha-imino keton for synthesizing chiral salbutamol
  • Method for asymmetrical hydrogen transfer of alpha-imino keton for synthesizing chiral salbutamol
  • Method for asymmetrical hydrogen transfer of alpha-imino keton for synthesizing chiral salbutamol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The first step is the preparation of methyl 5-(1,1-dihydroxy)-acetyl-2-hydroxybenzoate.

[0028] Add 75ml dimethyl sulfoxide (DMSO) in the 250ml three-necked bottle, 19.5g (0.1mol) methyl 5-acetyl salicylate, under room temperature, hydrobromic acid (HBr) 28ml (40%, 0.2mol, 2.0 eq) was added slowly, and the dropwise addition was completed in 40 minutes. The reaction solution was heated to 65° C., and reacted for about 20 hours. TLC detected that the raw material 5-acetyl salicylate methyl ester disappeared, and the reaction solution was slowly poured into 200 ml of ice water, and stirred for 30 Minutes, filtered, the solid was washed 3 times with 25ml of ice water, and vacuum-dried at room temperature to obtain 20.3g of the product 5-(1,1-dihydroxy)-acetyl-2-hydroxybenzoic acid methyl ester, with a yield of 90%. After further purification, it can be directly put into the next reaction.

[0029] The second step is the preparation of methyl 5-((1,1-dimethylethyl)imino)acet...

Embodiment 2

[0036] The first and second steps are the same as in Example 1.

[0037] The third step is the preparation of (S)-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoic acid methyl ester.

[0038] Under nitrogen protection, 0.26g (1mmol) of the compound obtained in the second step, (R, R)-Ru-TsDPEN6.4mg (0.01mmol), Et 3 Dissolve N 0.69ml (5.0mmol) in 2.0ml DMF, add HCOOH 0.07ml (2.0mmol) slowly, stir at room temperature for 24 hours, pour the reaction solution into 5.0ml water, extract twice with 10ml ethyl acetate, anhydrous sodium sulfate Drying, solvent evaporation under reduced pressure, and column chromatography to obtain the product (S)-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoic acid Methyl ester 0.13g, 96%ee, yield 48%.

[0039] The fourth step (S)-Salbutamol is: the preparation of (S)-2-(nitrogen-tert-butylamino)-1-(4-hydroxyl-3-hydroxymethylphenyl)ethanol

[0040] Under nitrogen protection condition, the product (S)-5-[2-[(1,1-dimeth...

Embodiment 3

[0042] The first, second and third steps are the same as in Example 1.

[0043] The fourth step is the preparation of (R)-Salbutamol: (R)-2-(nitrogen-tert-butylamino)-1-(4-hydroxyl-3-hydroxymethylphenyl)ethanol.

[0044] Under nitrogen protection condition, take by weighing the product 0.27g (1mmol) that the 3rd step makes, NaBH 4 95mg (2.5mmol), suspended in 10ml of anhydrous tetrahydrofuran (THF), slowly add BF dropwise at room temperature 3 .Et 2 O solution 0.4ml (content 47%, d, 1.13, 1.5mmol), after the dropwise addition, the reaction solution was heated to 55°C for 3 hours, then cooled to room temperature, methanol 4ml was added dropwise, and then the reaction solution was heated to 55°C for 1.5 Hours, down to room temperature, add N, N, N, N-tetramethylethylenediamine (TMEDA) 0.23ml (1.5mmol), after stirring at room temperature for 6 hours, filter, spin the solvent under reduced pressure, and column chromatography to obtain the product (R)-Salbutamol is 0.18g, 98%ee...

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Abstract

The invention relates to a method for synthesizing chiral albuterol by asymmetric hydrogen transfer of α-imino ketone, and relates to a new method for synthesizing optically pure-β aminoalcohol compound albuterol. First, methyl 5-acetyl salicylate is used as a raw material to be oxidized to methyl 5-(1,1-dihydroxy)-acetyl-2-hydroxybenzoate with an oxidizing reagent. Then react with tert-butylamine to obtain α-iminone compound. Then, using (S, S)-Ru-TsDPEN or (R, R)-Ru-TsDPEN as a catalyst, in formic acid, triethylamine, and an inert organic solvent system, asymmetric hydrogen transfer α-imino ketone compounds to obtain optical Pure product, namely: (R) or (S)-methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate. Finally, reduce (R) or (S)-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoic acid methyl ester to obtain optical Pure (R) or (S) chiral albuterol. The invention has good selectivity, mild reaction conditions, simple and convenient operation process and after-reaction treatment, is beneficial to repeated and expanded scale production, and has low cost.

Description

technical field [0001] The invention discloses a method for synthesizing chiral albuterol by asymmetric hydrogen transfer of α-iminone ketone, relates to a method for synthesizing optically pure-β amino alcohol compound salbutamol, and belongs to the technical field of chiral-β amino alcohol compound synthesis. Background technique [0002] Optically pure chiral aminoalcohols have shown increasing importance in medicinal and organic chemistry. In terms of medicinal chemistry, many aminoalcohol derivatives can be used as drugs, such as -βaminoarylethanol compounds are good medicines for the treatment of respiratory and cardiovascular diseases. A large number of medical practices have proved that only one optical isomer in racemic drugs has a better curative effect, and different enantiomers of chiral drugs often show different physiological activities. Therefore, for optically pure chiral β -Research on aminoarylethanol compounds is currently receivi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/60C07C213/00
Inventor 肖元晶谭宙宏杨琍苹
Owner EAST CHINA NORMAL UNIV
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