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A kind of preparation method of the intermediate of rasagiline

A technology for intermediates and compounds, applied in the field of preparation of intermediates, can solve the problems of producing by-product boric acid, ineffective utilization of by-products, environmental pollution, etc., and achieves the effects of low production cost, reduction of the elimination of three industrial wastes, and environmental friendliness.

Active Publication Date: 2011-12-14
CHIRAL QUEST (SUZHOU) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The technical problem to be solved by the present invention is in order to overcome the existing synthetic method of rasagiline, the product of (S)-configuration cannot be effectively utilized as a by-product and becomes a waste, and using sodium borohydride as a reducing agent produces A large amount of by-product boric acid has defects such as environmental pollution, and a preparation method of an intermediate of rasagiline is provided

Method used

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  • A kind of preparation method of the intermediate of rasagiline
  • A kind of preparation method of the intermediate of rasagiline
  • A kind of preparation method of the intermediate of rasagiline

Examples

Experimental program
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Effect test

Embodiment 1

[0041] In a 0.5-liter high-pressure reactor equipped with a thermometer and a stirrer, add acetyl enamine compound (III, X=H, Y=Me) (34.62 g, 0.2 mol) and methanol at room temperature (20-25 ° C). (120 mL), Rh / (RP , Sc)-Duanphos (136 mg, 0.1 mol%), and inject hydrogen to 10 atmospheres. Then heated to 40°C with stirring. HPLC traced the complete reaction of acetylene ss amines (48h). After the reaction, the reaction solution was concentrated and evaporated to remove the organic solvent to obtain (R)-1-acetylindenamine with a yield of 93%, a chemical purity of 99.7%, and an optical purity of 99.8% (HPLC). Then hydrolyze in aqueous sodium hydroxide solution, extract the aqueous phase with dichloromethane organic solvent, concentrate and evaporate the organic solvent, and distill under reduced pressure to obtain (R)-1-indenamine with a yield of 90%, a chemical purity of 99.4%, and an optical Purity 99.8% (HPLC). Using the obtained (R)-1-indenamine as a raw material, react with...

Embodiment 2

[0043] In a 0.5-liter high-pressure reactor equipped with a thermometer and a stirrer, add propionyl enamine compound (III, X=H, Y=Et) (37.44g, 0.2mol) at room temperature (20-25°C), three Fluoroethanol (150 mL), Rh / (Rp, Sc)-Duanphos (68 mg, 0.05 mol%), and hydrogen was injected to 15 atm. Then heated to 60°C with stirring. The reaction of propionyl enamines was followed by HPLC (30h). After the reaction, the reaction liquid was concentrated and evaporated to remove the organic solvent to obtain (R)-1-propionylindamide with a yield of 95%, a chemical purity of 99.8%, and an optical purity of 99.9% (HPLC). Then hydrolyze in aqueous potassium hydroxide solution, extract the aqueous phase with dichloromethane organic solvent, concentrate and evaporate the organic solvent, and distill under reduced pressure to obtain (R)-1-indenamine with a yield of 92%, a chemical purity of 99.7%, and an optical Purity 99.6% (HPLC).

Embodiment 3

[0045] In a 0.5-liter pressure reactor equipped with a thermometer and a stirrer, add acyl enamine compound (III, X=F, Y=Et) (41.04 g, 0.2 mol), tetrahydrofuran ( 180 mL), Rh / (Rp, Sc)-Duanphos (136 mg, 0.1 mol%), and inject hydrogen to 1 atmosphere. Stir at room temperature (20° C.) until the reaction of the propionyl enamine compound is complete (96 h) as tracked by HPLC. After the reaction, the reaction liquid was concentrated and evaporated to remove the organic solvent to obtain the corresponding (R)-5-fluoro-1-propionylindamide with a yield of 90%, a chemical purity of 99.4%, and an optical purity of 99.7% (HPLC). Then hydrolyze in aqueous sodium hydroxide solution, extract the aqueous phase with dichloromethane organic solvent, concentrate and evaporate the organic solvent, and distill under reduced pressure to obtain 5-fluoro-1-indenamine with a yield of 85%, a chemical purity of 99.1%, and an optical Purity 99.6% (HPLC).

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Abstract

The invention discloses a method for preparing a midbody compound of rasagiline shown as the formula IV described in the specification. The method comprises the step of carrying out asymmetric catalysis hydrogenation reaction of a compound III and hydrogen in an organic solvent by taking one or more of Rh / (Rc,Sp)-Duanphos, Rh / (S,S,R,R)-Tangphos and Rh / (S)-Binapine as catalyst, wherein X is H, halogen, C1-C5 alkyl or C1-C5 alkoxy; and Y is C1-C5 alkyl or trifluoromethyl. According to the preparation method disclosed by the invention, both the yield and the purity of the product are higher; and method has the advantages of simpleness and convenience for operation, low cost, environment friendliness and easiness industrialization.

Description

technical field [0001] The present invention specifically relates to a preparation method of an intermediate of rasagiline. Background technique [0002] Rasagiline (Rasagiline), the chemical name is (R)-(+)-N-propargyl-1-indenamine, which is jointly developed by Lunbeck Company and Teva Company for single or auxiliary levodopa treatment. Drugs for Kinson's disease. Rasagiline was launched in Europe in February 2005 and was approved by the US FDA. The medicine has small toxic and side effects, high efficacy, good selectivity and good market prospect. [0003] At present, the synthesis method of rasagiline is to first synthesize the racemate N-propargyl-1-indenamine. N-propargyl-1-indenamine is then resolved (R)-(+)-N-propargyl-1-indenamine and (S )-(-)-1-N-propargyl-1-indenamine. The (S)-configuration product is a by-product and cannot be effectively utilized as waste. In addition, chiral phenethylamine is used as a raw material to obtain (R)-(+)-N-propargyl-1-indenyla...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C233/06C07C233/14C07C233/23C07C209/62C07C211/42C07C213/02C07C217/74
Inventor 刘国斌刘军涛黄晓飞廖海秀
Owner CHIRAL QUEST (SUZHOU) CO LTD
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