Preparation method of phenyl (S)-N-ethyl-N-methyl-3-[1-(dimethyamino)ethyl]-amidoformate (I) and tartrate thereof (II)

A technology of phenyl carbamate and dimethylamino, applied in (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (I) The preparation field of its tartrate (II) can solve the problems of low total yield, waste, and high cost, and achieve the effects of simple operation, high optical purity, and convenient source of raw materials

Inactive Publication Date: 2007-03-07
SHANGHAI AOBO PHARMTECH INC LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] These resolution methods mean that at least 50% of the (R)-isome

Method used

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  • Preparation method of phenyl (S)-N-ethyl-N-methyl-3-[1-(dimethyamino)ethyl]-amidoformate (I) and tartrate thereof (II)
  • Preparation method of phenyl (S)-N-ethyl-N-methyl-3-[1-(dimethyamino)ethyl]-amidoformate (I) and tartrate thereof (II)
  • Preparation method of phenyl (S)-N-ethyl-N-methyl-3-[1-(dimethyamino)ethyl]-amidoformate (I) and tartrate thereof (II)

Examples

Experimental program
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Embodiment 1

[0043] Example 1 Preparation of 3-(1-(S)-(N,N-dimethylamino)ethyl)-phenyl chloroformate

[0044] Dissolve triphosgene (15.9g, 53.5mmol) in 400ml tetrahydrofuran, and add 3-(1-(S)-(N,N-dimethylamino)ethyl)-sodium phenoxide ( 25g, 133.7mmol), stirred at 0°C for 20 minutes, then heated to 55-60°C for four hours, blown off the remaining phosgene with nitrogen, filtered off sodium chloride, and concentrated to obtain an oily liquid (30g). Without purification, directly into the next reaction.

Embodiment 2

[0045] The preparation of embodiment two rivastigmine

[0046] Under ice-water bath cooling, the oily liquid (30g) obtained in Example 1 was dissolved in 200ml of anhydrous ether, and this solution was added dropwise to triethylamine (18.7mL), methylethylamine (7.9g, 133.7mmol) and 300mL of anhydrous ether mixture. Stirring was continued for 20 minutes under ice-cooling, and then reacted overnight at room temperature. Remove triethylamine hydrochloride by filtration, wash with saturated brine (2×200mL), dry over anhydrous sodium sulfate, concentrate to obtain a colorless oily liquid, distill under reduced pressure, and collect fractions at 120-122°C (about 0.5 mm Hg) , to get rivastigmine (26.8g, two-step yield 80%).

Embodiment 3

[0047] Example 3 Preparation of 3-(1-(S)-(N,N-dimethylamino)ethyl)-phenyl chloroformate

[0048] Sodium hydroxide (3.18g, 79.5mmol) was dissolved in 100mL ethanol, and slowly added dropwise to 3-(1-(S)-(N,N-dimethylamino)ethyl)-phenol hydrochloride ( 8g, 39.7mmol) in 100mL of ethanol, stirred at room temperature for 1 hour, concentrated and evaporated to dryness of ethanol and water. The resulting solid was slowly added to a solution of triphosgene (4.7 g, 15.9 mmol) in tetrahydrofuran (120 mL) cooled in an ice-salt bath, stirred at 0° C. for 20 minutes, then heated to 55-60° C. for four hours, and blown away with nitrogen. Phosgene, sodium chloride was filtered off, and concentrated to give an oily liquid (9g). Without purification, rivastigmine can be directly reacted with methylethylamine to prepare rivastigmine (operation steps refer to Example 2).

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Abstract

The invention discloses (S)-N-ethyl-N-methyl-3[1-(dimethylamino) ethyl]-carbamidbenzoate (I) and preparing method of tartrate (II), which comprises the following steps: reacting compound (III) or salt and phosgene, diphosgene or triphosgene to obtain compound (IV); preparing compound (I) through reacting non-purifying compound (IV) and N-methyl-N-ethyl ammonium; reacting compound (I) and L-(+)-tartaric acid to obtain tartrate (II).

Description

technical field [0001] The present invention relates to a new synthesis of (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-carbamic acid phenyl ester (1) and its tartrate (II) method. Background technique [0002] Alzheimer's disease (abbreviated as AD) is a neurological disease caused by the death of brain nerve cells. Its symptoms are mainly the loss of memory and cognitive ability of the patient in varying degrees, and the disturbance of behavioral activities. [0003] Rivastigmine (Rivastigmine, chemical name (S)-N-ethyl-N-methyl-3-[1-(dimethylamino) ethyl]-carbamic acid phenyl ester) (I), and its tartrate ( II) has the following structural formula: [0004] [0005] Rivastigmine tartrate (II) is an effective drug used to alleviate the development of AD. Its mechanism of action is to inhibit acetylcholinesterase in the human brain and increase the content of acetylcholine in the central nervous system. It is suitable for mild to moderate patients The treatment can ...

Claims

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Application Information

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IPC IPC(8): C07C271/46C07C269/04
CPCC07C269/04C07C211/49C07C211/29A61P25/28C07C271/44
Inventor 马大为潘强彪潘嵩
Owner SHANGHAI AOBO PHARMTECH INC LTD
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