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A kind of preparation method of rivastigmine

A synthesis method and technology of protecting groups, which are applied in the field of asymmetric synthesis of rivastigmine, can solve the problems of unrecoverable chiral inducer, poor atom economy, large amount of waste, etc., and achieve environmental friendliness, low cost and low cost. Effect

Inactive Publication Date: 2011-12-21
CHENGDU INST OF BIOLOGY CHINESE ACAD OF S
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Problems solved by technology

[0010] The reagents used in the resolution method are relatively cheap, but only half of the racemate can be utilized, and the other configuration is wasted, resulting in high cost and a large amount of waste; while the chiral induction synthesis method requires the use of a stoichiometric chiral inducer, and Chiral inducers cannot be recycled, poor atom economy and high cost

Method used

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  • A kind of preparation method of rivastigmine
  • A kind of preparation method of rivastigmine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: the synthesis of (S)-1-m-methoxyphenylethylamine

[0030] (1) Synthesis of N-o-methoxyphenyl m-methoxyacetophenone imine

[0031] Under normal pressure and nitrogen protection, m-methoxyacetophenone (1.50 g, 10.0 mmol) and o-methoxyphenylamine (1.23 g, 10.0 mmol) were dissolved in toluene, and stirred at 0° C. for about 5 h. After the completion of the reaction as monitored by TLC, filter, wash with toluene (3×30 mL), and evaporate the solvent under reduced pressure to obtain 2.31 g of N-o-methoxyphenyl m-methoxyacetophenone imine, which is a light yellow solid with a yield of 90%. .

[0032](2) Synthesis of (S)-N-o-methoxyphenyl m-methoxyphenylethylamine

[0033] Under normal pressure and nitrogen protection, N-tert-butylsulfinylproline-2,6-diisopropylphenylamide catalyst (344mg, 0.91mmol) and N-o-methoxyphenyl m-methoxy Acetophenoneimine (2.31g, 9.06mmol) was mixed in toluene (20mL), cooled to 0°C, trichlorosilane (1.8mL, 18.1mmol) was added slowly, a...

Embodiment 2

[0036] Embodiment 2: the synthesis of (S)-1-m-methoxyphenylethylamine

[0037] (1) Synthesis of N-methoxyphenyl m-methoxyacetophenone imine

[0038] Under normal pressure and nitrogen protection, m-methoxyacetophenone (1.50 g, 10.0 mmol) and m-methoxyphenylamine (1.23 g, 10.0 mmol) were dissolved in toluene, and stirred at 0° C. for about 12 h. The post-treatment was the same as in Example 1 to obtain 2.34 g of N-m-methoxyphenyl-m-methoxyacetophenone imine as a pale yellow solid with a yield of 91%.

[0039] (2) Synthesis of (S)-N-m-methoxyphenyl-m-methoxyphenylethylamine

[0040] Under normal pressure and nitrogen protection, N-tert-butylsulfinyl proline tert-butyl amide catalyst (226mg, 0.86mmol) and N-methoxyphenyl m-methoxyacetophenone imine (2.34g , 9.18mmol) were mixed in carbon tetrachloride (20mL), cooled to -5°C, trichlorosilane (1.61mL, 16.1mmol) was added slowly, and reacted at -5°C for 10h. The specific operation steps were the same as in Example 1 to obtain 2.1...

Embodiment 3

[0043] Embodiment 3: the synthesis of (S)-1-m-methoxyphenylethylamine

[0044] (1) Synthesis of (S)-N-p-methoxyphenyl m-methoxyacetophenone imine

[0045] Under normal pressure and nitrogen protection, m-methoxyacetophenone (1.50 g, 10.0 mmol) and p-methoxyphenylamine (1.23 g, 10.0 mmol) were dissolved in dichloromethane, and stirred at 0° C. for about 5 h. The post-treatment was the same as in Example 1 to obtain 2.37 g of N-p-methoxyphenyl m-methoxyacetophenone imine as a light yellow solid with a yield of 92%.

[0046] (2) Synthesis of (S)-N-p-methoxyphenyl m-methoxyphenylethylamine

[0047] Under normal pressure and nitrogen protection, N-tert-butylsulfinylproline benzylamide catalyst (215mg, 0.698mmol) and N-p-methoxyphenyl m-methoxyacetophenone imine (2.37g, 9.3mmol) was mixed in dichloromethane (20mL), cooled to -10°C, trichlorosilane (1.40mL, 13.95mmol) was added slowly, and reacted at -10°C for 10h. The specific operation steps were the same as in Example 1 to obta...

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Abstract

The invention belongs to the technical field of organic chemistry, and particularly relates to a method for preparing a key chiral amine intermediate of rivastigmine through reduction of chiral organic small molecular catalytic imine and finally realizing asymmetric synthesis of the rivastigmine. The method is realized through the following ways of: performing asymmetric catalytic hydrogen transfer reduction on meta-methoxyl acetophenone imine with methoxyphenyl or benzyl protective groups on N atoms to prepare (S)-meta-methoxyphenyl ethyl amine with the methoxyphenyl or benzyl protective groups on the N atoms; removing the protective groups on the N atoms of the (S)-meta-methoxyphenyl ethyl amine with the methoxyphenyl or benzyl protective groups on the N atoms by using a ceric ammonium nitrate oxidation or catalytic hydrogenation protective group removal method respectively to prepare (S)-meta-methoxyphenyl ethyl amine; and performing amino dimethylation reaction on the (S)-meta-methoxyphenyl ethyl amine, formaldehyde and Pd / C through catalytic hydrogenation, reacting the (S)-meta-methoxyphenyl ethyl amine with hydrobromic acid to perform deprotection of the methoxyl group, and finally performing phenolic hydroxyl ammonia formylation reaction on the (S)-meta-methoxyphenyl ethyl amine and N-ethyl-N-methyl carbamoyl chloride to prepare the rivastigmine. The method has the advantages of low manufacturing cost of a chiral catalyst, easiness in preparation, small loading capacity, high yield and enantioselectivitiy, environmental friendliness and low comprehensive cost and issuitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and specifically relates to the preparation of key chiral amine intermediates of rivastigmine by using chiral organic small molecules to catalyze the reduction of imines, and finally realize the asymmetric synthesis of rivastigmine. Background technique [0002] Rivastigmine (Rivastigmine), chemical name (S)-N-ethyl-3-[(1-dimethylamino)acetyl]-N-methylcarbamate phenyl ester, also known as Esner, Liss It is a chiral amine drug with (R)- and (S)-two enantiomers, and the S configuration is its active ingredient. It is a new type of anti-senile dementia drug developed by Novartis, Switzerland. It has a more significant effect on advanced patients. It is currently the drug with the highest international evaluation for improving the symptoms of Alzheimer's dementia. It belongs to the third generation of drugs for improving the function of the choline system. It is a carbamate-type reversible...

Claims

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Application Information

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IPC IPC(8): C07C271/44C07C269/00C07C217/58C07C213/08
CPCY02P20/55
Inventor 孙健李扬王超
Owner CHENGDU INST OF BIOLOGY CHINESE ACAD OF S
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