Background and overview[1]
Rivastigmine is an acetylcholinesterase inhibitor with the trade name Exelon, produced by Novartis Pharmaceuticals Company of the United States. The FDA approved the oral liquid and capsules of this product for the treatment of Alzheimer’s disease on April 21, 2000. The drug has been approved for sale in 70 countries including EU countries, Switzerland, New Zealand, Australia, Canada and Mexico. 1-(3-Methoxyphenyl)ethylamine is the key intermediate of rivastigmine.
Preparation method[1]
The literature Bull.Chem.Soc.Jpn., 66, 3414-3418 reports that the method is to use S-mandelic acid to resolve racemic 1-(3-methoxyphenyl)ethylamine. The synthesis route is as follows:
Relatively speaking, this method has the following shortcomings:
The S-mandelic acid used as a resolving agent has an unsatisfactory effect and a low yield of only 21.7%.
CN200610116949.3 provides a new method for preparing optically active 1-(3-methoxyphenyl)ethylamine, the key intermediate of rivastigmine, which method includes making m-methoxyacetophenone The step is to perform an asymmetric reductive amination reaction with optically active phenylethylamine in an organic solvent under a combined reduction system. Subsequently, a debenzylation reaction is performed to obtain optically active 1-(3-methoxyphenyl)ethylamine. The synthesis route is as follows:
The specific preparation method includes the following steps:
Conduct an asymmetric reductive amination reaction between m-methoxyacetophenone, optically active phenylethylamine and tetraalkyl titanate in the presence of Raney-Ni in an organic solvent under a certain pressure. After the reaction is completed Filter out the Raney-Ni catalyst, add 1N sodium hydroxide aqueous solution to neutralize, recover the organic solvent after liquid separation, and then use the palladium carbon hydrogenation catalyst to remove benzylation, then filter out the palladium carbon hydrogenation catalyst, recover the organic solvent, and collect the target product optical The active 1-(3-methoxyphenyl)ethylamine has a yield of more than 75% and an optical purity of more than 99%. 1HNMR(CDCl3)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).
The preparation of optically active 1-(3-methoxyphenyl)ethylamine by the method of the present invention has the following advantages:
1. Use a tetraalkyl titanate/Raney-Ni/H2 combination system to perform an asymmetric reductive amination reaction followed by a debenzylation reaction to prepare optically active 1-(3-methoxyphenyl)ethylamine. The total yield reaches more than 75%.
The optical purity of 2.1-(3-methoxyphenyl)ethylamine is greater than 99%.
Main reference materials
[1] CN200610116949.3 Preparation method of optically active 1-(3-methoxyphenyl)ethylamine
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