Synthesis process of (S)-rivastigmine

A synthesis method and compound technology, applied in the field of chiral drug synthesis, can solve problems such as the use of toxic and harmful reagents, many steps, complex processes, etc., and achieve the effects of easy industrial production, mild reaction conditions, and high reaction yield

A synthesis method and compound technology, applied in the field of chiral drug synthesis, can solve problems such as the use of toxic and harmful reagents, many steps, complex processes, etc., and achieve the effects of easy industrial production, mild reaction conditions, and high reaction yield

CN103304447AActive Publication Date: 2013-09-18YABAO PHARMA GRP CO LTD
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  • Synthesis process of (S)-rivastigmine

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Embodiment 1

[0044] Synthesis of 3-acetylphenyl N-ethyl-N-methyl-carbamate (2)

[0045] Under nitrogen protection at 25°C, m-hydroxyacetophenone (1) (99.0%, 20.0g, 147mmol, 1eq) was dissolved in acetone (AR, 400mL), anhydrous potassium carbonate (AR, 40.6g, 294mmol) was added under stirring , 2eq), slowly added methylethylcarbamoyl chloride (99.4%, 21.4g, 176mmol, 1.2eq) dropwise. 50 ℃ reaction 4h, stop the reaction. The reaction solution was pumped to remove the anhydrous potassium carbonate solid, water (400 mL) was added to the filtrate, extracted with ethyl acetate (250 mL×3), the organic phase was dried with anhydrous magnesium sulfate, and the water pump was spin-dried under reduced pressure to obtain a yellow oil The product N-ethyl-N-methyl-carbamic acid 3-acetylphenyl ester (2) (34.22 g, yield 90%).

[0046] 1HNMR (CDC13) δ1.24(m, 3H, CCH3), 2.61(s, 3H, CCH3), 3.06(d, 3H,, NCH3), 3.47(m, 2H, CH2), 7.35(d, 1H, ArH ), 7.47 (s, 1H, ArH), 7.71 (d, 1H, ArH), 7.80 (t, 1H, ArH); MS, m...

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Abstract

The invention discloses an unsymmetrical synthesis method of (S)-rivastigmine. The method comprises the following steps of: reacting hydroxyacetophenone with methylethylcarbamoyl chloride to generate N-ethyl-N-methyl-carbamate 3-acetylphenyl formate, carrying out chiral reduction on the N-ethyl-N-methyl-carbamate 3-acetylphenyl formate under the catalysis effect of a complex of (S)-(-)-alpha, alpha-diphenyl prolinol and trimethyl borate, carrying out methanol dissociation to generate N-ethyl-N-methyl- carbamate 3-[(R)-1-hydroxyethyl]phenyl formate, and reacting the N-ethyl-N-methyl- carbamate 3-[(R)-1-hydroxyethyl]phenyl formate with methylsufonyl chloride and dimethylamine hydrochloride to obtain the (S)-rivastigmine. According to the method disclosed by the invention, a target product can be prepared from conventional reagents only through a three-step reaction, the reaction yield reaches 40% and is far higher than that by a racemic resolution method and that by other chiral synthesis methods, the application of virulent reagents and highly corrosive reagents are avoided in the process, and the unsymmetrical synthesis method is easy to operate, environment-friendly, low in production cost, and suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of chiral drug synthesis, in particular to a method for synthesizing optically pure (S)-rivastigmine, specifically an asymmetric synthesis method of (S)-rivastigmine. Background technique [0002] Exelon (Exelon) is a new type of carbamate brain-selective cholinesterase inhibitor that was launched in 1997 for the treatment of senile dementia. It is the second generation drug for the treatment of senile dementia. Its active ingredient: rivastigmine bitartrate (rivastigmine), is an amino acid formic acid brain tissue selective cholinesterase inhibitor, although the half-life of the drug is relatively short, but the inhibitory effect on cholinesterase can reach 10 hours, the The drug promotes cholinergic nerve conduction by delaying the degradation of acetylcholine released by cholinergic neurons, thereby increasing the content of acetylcholine. Rivastigmine hydrogentartrate, the chemical name is N-ethyl-N-met...

Claims

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Application Information

Patent Timeline
18 Sep 2013
Publication
CN103304447A
IPC
C07C271/44; C07C269/06
CPC
Y02P20/582
Inventors
张海军; 接传明