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Method for synthesis of (S)-rivastigmine through reductive amination

A synthesis method and compound technology, which are applied in the field of chiral drug synthesis in pharmaceutical and chemical industry, can solve the problems of unsatisfactory yield, expensive starting materials, harsh reaction conditions, etc., and achieve short synthesis steps and good industrial application. Prospect, effect of fewer reaction steps

Inactive Publication Date: 2018-11-16
SHANDONG NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] Compared with the resolution method, the yield of the asymmetric synthesis method is obviously improved, but the yield still does not meet the needs of production, and the asymmetric synthesis method reported at present has expensive starting materials (or chiral raw materials) and reaction conditions. Disadvantages such as harshness or the use of environmentally unfriendly reagents

Method used

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  • Method for synthesis of (S)-rivastigmine through reductive amination
  • Method for synthesis of (S)-rivastigmine through reductive amination
  • Method for synthesis of (S)-rivastigmine through reductive amination

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] (1) Synthesis of N-methylethyl (3-acetylphenyl) carbamate (compound 3)

[0132] 3-Hydroxyacetophenone (5.1g, 38mmol) and methylethylcarbamoyl chloride (7.2g, 58mmol) were added to acetone (100mL) in turn. After the reaction solution was dissolved, potassium carbonate (10.4g, 76mmol) was added. After the addition, the temperature was raised to 60°C, and the reaction was stirred for 4 hours. After the reaction was completed, the temperature was lowered to room temperature, filtered, and the filter cake was washed with acetone (20 mL). The filtrate was concentrated under reduced pressure to obtain a light yellow oily compound 3 (with 3-hydroxyacetophenone Total, the yield is 100%). 1 H-NMR (500MHz, Chloroform-d): δ7.83(d,J=7.7Hz,1H), 7.74(s,1H), 7.50(t,J=7.9Hz,1H), 7.39(s,1H) , 3.50(dq,J=35.8,7.1Hz,2H), 3.09(d,J=42.1Hz,3H), 2.64(s,3H), 1.28(dt,J=29.2,7.1Hz,3H)

[0133] (2) Synthesis of (Compound 4)

[0134] Compound 3 (221mg, 1mmol) and benzhydrylamine (238mg, 1.3mmol) were add...

Embodiment 2

[0140] (1) Synthesis of N-methylethyl (3-acetylphenyl) carbamate (compound 3)

[0141] 3-Hydroxyacetophenone (5.1g, 38mmol) and methylethylcarbamoyl chloride (7.2g, 58mmol) were added to ethyl acetate (80mL) in turn. After the reaction solution was dissolved, triethylamine (4.04g, 40mmol), after the addition, the temperature was raised to 40°C, stirred for 7 hours, after the reaction was completed, cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (25mL), and the filtrate was concentrated under reduced pressure to obtain a light yellow oily compound 3 (with 3 -Based on hydroxyacetophenone, the yield is 100%).

[0142] (2) Synthesis of (Compound 4)

[0143] Compound 3 (221mg, 1mmol) and benzhydrylamine (366mg, 2.0mmol) were sequentially added to stirring acetone (10mL). After the reaction solution was dissolved, formic acid (0.8mmol) and tetraethyl titanate (0.5mmol) were added. , Then add Ir catalyst (22.1mg) and molecular sieves, place the rea...

Embodiment 3

[0149] (1) Synthesis of N-methylethyl (3-acetylphenyl) carbamate (compound 3)

[0150] 3-Hydroxyacetophenone (5.1g, 38mmol) and methylethylcarbamoyl chloride (7.2g, 58mmol) were added to toluene (150mL) in sequence. After the reaction solution was dissolved, diisopropylethylamine (5.17 g, 40mmol), after the addition, the temperature was raised to 80°C, the reaction was stirred for 2.5 hours, the reaction was completed, the temperature was lowered to room temperature, filtered, the filter cake was washed with toluene (30mL), the filtrate was concentrated under reduced pressure to obtain a light yellow oily compound 3 (with 3 -Based on hydroxyacetophenone, the yield is 96%).

[0151] (2) Synthesis of (Compound 4)

[0152] Compound 3 (221mg, 1mmol) and benzhydrylamine (238mg, 1.3mmol) were added to the stirring dichloromethane (15mL) in turn, the reaction solution was dissolved and added p-nitrobenzoic acid (0.2mmol) and titanate Isobutyl ester (0.5mmol), then add Ir catalyst (22.1mg)...

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Abstract

The invention provides a method for ynthesis of (S)-rivastigmine through reductive amination, belonging to the technical field of synthesis of chiral medicines in the pharmaceutical and chemical industry. The synthetic method of the invention comprises the following steps: with 3-hydroxyacetophenone as a raw material, carrying out a simple condensation reaction so as to realize high-yield preparation of 3-nitromethylethylformate acetophenone; then with 3-nitromethylethylformate acetophenone as a substrate, carrying out an asymmetric reductive amination reaction with benzhydrylamine under the catalysis of an Ir complex so as to obtain a chiral amine precursor with high enantioselectivity and high yield; and then carrying out deprotection and a methylation reaction so as to obtain (S)-rivastigmine with high enantioselectivity and high yield. The synthetic route of the method is short; the total yield of four steps can reach 80%; the enantioselective excess of (S)-rivastigmine can reach 98%; so the method has good industrial application prospects and practical application value.

Description

Technical field [0001] The invention belongs to the technical field of chiral drug synthesis in medicine and chemical industry, and relates to a preparation method of anti-senile dementia drug (S)-rivastigmine, in particular to a method for reductive amination to synthesize (S)-rivastigmine. Background technique [0002] Alzheimer's disease (AD) is a degenerative disease of the central nervous system. It is clinically characterized by cognitive impairments such as memory impairment, aphasia, cognition, and executive function, as well as mental Abnormal behavior and obvious decline in social life function. Neuropathological studies have shown that the distinguishing features of this disease are neurofibrillary tangles and extracellular neuritic plaques in the cerebral cortex and large areas below, or senile amyloid deposit plaques. [0003] Rivastigmine, whose chemical name is (S)-N-ethyl-3-[(1-dimethylamino)acetyl]-N-methylcarbamic acid phenyl ester, is a chiral amine drug with (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/44C07C269/00C07C269/06A61P25/28
Inventor 高国锐常明欣
Owner SHANDONG NORMAL UNIV
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