Method for preparing optical active 1-(3-methoxy phenyl) ethylamine

A technology of methoxyphenyl and methoxyacetophenone, which is applied in the field of medicinal chemistry, can solve the problems of unsatisfactory effect and low yield, and achieve the effects of mild conditions, high reaction yield and simple post-treatment

Inactive Publication Date: 2008-04-16
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The S-mandelic acid that uses is as resolving agent,

Method used

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  • Method for preparing optical active 1-(3-methoxy phenyl) ethylamine
  • Method for preparing optical active 1-(3-methoxy phenyl) ethylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Put 6g (0.04mol) of m-methoxyacetophenone, 4.84g (0.04mol) of S-phenethylamine and 11.36g (0.04mol) of tetraisopropyl titanate into the hydrogenation kettle, add 100ml methanol and Raney-Ni 1.8 g, react at an internal temperature of 80C and a pressure of 3 atm until the pressure does not drop, filter the discharge to remove Raney-Ni, add 40ml of 1N sodium hydroxide to the filtrate and recover methanol, extract the residue with 50ml of ethyl acetate, recover ethyl acetate and add 50ml Methanol and 10% Pd / C 1.2g, debenzylation at 60°C and 3 atm, filter off the Pd / C catalyst after the reaction is complete, collect the target product S-1-(3-methoxyphenyl)ethylamine after recovering the solvent 4.53 g, yield 75%. 1 HNMR (CDCl 3 )δ: 1.36 (d, 2H,), 3.80 (S, 3H), 4.05 (q, 1H,), 6.76~7.22 (m, 4H); ESI (m / z): 152 (M+1); (C2, MeOH).

Embodiment 2

[0027] Put 12g (0.08mol) of m-methoxyacetophenone, 11.62g (0.096mol) of S-phenethylamine and 36.48g (0.16mol) of tetraethyl titanate into the hydrogenation kettle, add 200m ethyl acetate and Raney-Ni7 .2g, react at an internal temperature of 60°C and a pressure of 5 atm until the pressure does not drop, filter the discharge to remove Raney-Ni, add 80ml of 1N sodium hydroxide to the filtrate and separate the liquid, add 200ml of ethanol and 5% Pd / C4 after recovering ethyl acetate .8g, debenzylation at 60°C and 3atm. After the reaction was complete, the Pd / C catalyst was filtered off. After recovering the solvent, 9.66g of the target product S-1-(3-methoxyphenyl)ethylamine was collected, with a yield of 80%.

Embodiment 3

[0029] Put 6g (0.04mol) of m-methoxyacetophenone, 6.3g (0.052mol) of R-phenethylamine and 68g (0.2mol) of tetrabutyl titanate into the hydrogenation kettle, add 100ml of tetrahydrofuran and 6g of Raney-Ni, React at a temperature of 70°C and a pressure of 10 atm until the pressure does not drop, filter the discharge to remove Raney-Ni, add 200ml of 1N sodium hydroxide to the filtrate and recover tetrahydrofuran, extract the residue with 50ml of ethyl acetate, add 50ml of methanol and 10 %Pd / C 1.2g, debenzylation at 60°C and 3 atm, filter off the Pd / C catalyst after the reaction is complete, collect the target product R-1-(3-methoxyphenyl)ethylamine 4.59g after recovering the solvent, and obtain rate of 76%.

[0030] 1 HNMR (CDCl 3 )δ: 1.37 (d, 2H,), 3.80 (S, 3H), 4.08 (q, 1H,), 6.76~7.22 (m, 4H); ESI (m / z): 152 (M+1); (C2, MeOH).

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Abstract

The invention discloses a preparation method of an optical-active intermidiate compound 1-(3-methoxyphenyl)ethylamine, which includes the procedure to use M-methoxylacetophenone and optical-active phenylethylamine to carry out an asymmetric reducing aminating reaction undergoing in a combined reduction system in an organic solvent. The invention has a total yield above 75 percent, with the optic purity higher than percent, and simple preparation method in favor of large-scale production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of optically active 1-(3-methoxyphenyl)ethylamine, a key intermediate of rivastigmine, which is a medicine for treating Alzheimer's disease. Background technique [0002] Rivastigmine (rivastigmine) is an acetylcholinesterase inhibitor with a trade name of Exelon, produced by Novartis Pharmaceuticals of the United States. The FDA approved the oral liquid and capsules of this product on April 21, 2000, for the treatment of Alzheimer's disease. The drug has been approved for sale in 70 countries including EU countries, Switzerland, New Zealand, Australia, Canada and Mexico. [0003] Synthesis of 1-(3-methoxyphenyl) ethylamine of rivastigmine key intermediate optical activity, document Bull.Chem.Soc.Jpn., 66,3414-3418 report method is to use S-mandelic acid For the resolution of racemic 1-(3-methoxyphenyl)ethylamine, the synthetic route is as follows: [00...

Claims

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Application Information

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IPC IPC(8): C07C217/58C07C213/02
CPCC07C213/08C07B2200/07
Inventor 张福利胡猛谢美华
Owner SHANGHAI INST OF PHARMA IND
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