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Preparation method of rasagiline mesylate and intermediate thereof

A technology of rasagiline mesylate and intermediates, which is applied in the field of preparation of rasagiline mesylate and intermediates thereof, can solve the problems of many side reactions, low reaction yield and high impurity content

Active Publication Date: 2019-01-11
上海新礼泰药业有限公司
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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 harsh reaction conditions, many side reactions, high impurity content, low reaction yield, low purity of the prepared product, and low purity of the prepared product of rasagiline mesylate in the prior art. According to the raw material drug standard, it is not suitable for defects such as industrial production and provides a preparation method for rasagiline mesylate and its intermediates

Method used

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  • Preparation method of rasagiline mesylate and intermediate thereof
  • Preparation method of rasagiline mesylate and intermediate thereof
  • Preparation method of rasagiline mesylate and intermediate thereof

Examples

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Embodiment 1

[0066] Embodiment 1: the preparation of rasagiline intermediate II

[0067]

[0068] Under nitrogen protection, add (R)-(-)-1-aminoindane 22g (0.165mol) and propiolic acid 16.2g (0.231mol) into 440mL of dichloromethane, and add dicyclohexylcarbodiethylene 57.8g (0.280mol) of amine and 36.3g (0.297mol) of 4-dimethylaminopyridine were stirred at 15-20°C for 3-4 hours. A 12% hydrochloric acid aqueous solution was added to quench (the stated mass concentration refers to the percentage of the mass of hydrogen chloride in the total mass of the hydrochloric acid aqueous solution), and then extracted with dichloromethane. The mass concentration of the organic phase is 10% aqueous sodium hydroxide solution (the mass concentration refers to the percentage of the quality of sodium hydroxide in the total mass of the aqueous sodium hydroxide solution), and the mass concentration is 10% aqueous sodium bicarbonate solution (the mass concentration of the Concentration refers to that the q...

Embodiment 2

[0069] Embodiment 2: the preparation of rasagiline intermediate II

[0070] Under the protection of nitrogen, add 33g (0.248mol) of (R)-(-)-1-aminoindane and 22.1g (0.315mol) of propiolic acid to 495mL of tetrahydrofuran, and add 1-hydroxybenzotriazole 42.7g under stirring. g (0.316 mol), 62.7 g (0.327 mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and then 37.6 g (0.621 mol) of triethylamine were added. Stir at 20-25°C for 2-3 hours. A 12% hydrochloric acid aqueous solution was added to quench (the stated mass concentration refers to the percentage of the mass of hydrogen chloride in the total mass of the hydrochloric acid aqueous solution), and then extracted with dichloromethane. The mass concentration of the organic phase is 10% aqueous sodium hydroxide solution (the mass concentration refers to the percentage of the quality of sodium hydroxide in the total mass of the aqueous sodium hydroxide solution), and the mass concentration is 10% aqueous sodium...

Embodiment 3

[0071] Embodiment 3: the preparation of rasagiline intermediate II

[0072] Under nitrogen protection, add (R)-(-)-1-aminoindan 22g (0.165mol) and propiolic acid 12.7g (0.181mol) to 220mL of 2-methyltetrahydrofuran, and add O-(7 -Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 68.9g (0.181mol), then add diisopropylethylamine 31.9g ( 0.247mol). Stir at 10-15°C for 1-2 hours. A 12% hydrochloric acid aqueous solution was added to quench (the stated mass concentration refers to the percentage of the mass of hydrogen chloride in the total mass of the hydrochloric acid aqueous solution), and then extracted with dichloromethane. The mass concentration of the organic phase is 10% aqueous sodium hydroxide solution (the mass concentration refers to the percentage of the quality of sodium hydroxide in the total mass of the aqueous sodium hydroxide solution), and the mass concentration is 10% aqueous sodium bicarbonate solution (the mass concentration described is...

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Abstract

The invention discloses a preparation method of rasagiline mesylate and an intermediate thereof. The invention provides the preparation method of rasagiline mesylate I. The preparation method comprises the following steps: S1, in an organic solvent, in the presence of a reducer and a catalyst, carrying out a reduction reaction on a rasagiline mesylate intermediate II and the reducer to obtain a rasagiline mesylate intermediate III; and S2, in an organic solvent, carrying out a salt forming reaction on the rasagiline mesylate intermediate III obtained in the S1 and methanesulfonic acid to obtain rasagiline mesylate I. The preparation method does not employ an amino alkylation reaction which is relatively more in side reaction, and the prepared rasagiline mesylate I is high in purity, reaches the demand on bulk pharmaceutical chemicals, the purity is greater than 99.5%, the maximum single impurities are smaller than 0.10%, the yield is high, the production cost is low, and the method issuitable for industrial production. The formula is as shown in the description.

Description

technical field [0001] The invention relates to a preparation method of rasagiline mesylate and an intermediate thereof. Background technique [0002] Rasagiline mesilate (I) was developed by Israel’s Teva Pharmaceutical Industries, and was first approved for marketing by the European Medicines Agency (EMA) on February 21, 2005 and on May 16, 2006. It was approved by the U.S. Food and Drug Administration (FDA) on the 1st and marketed by Teva under the product name Azilect. Rasagiline mesylate is an irreversible monoamine oxidase inhibitor. By selectively inhibiting monoamine oxidase, it can reduce the decomposition of dopamine and increase the extracellular level of dopamine in the hyperstriatum of the brain. The increased dopamine level can reduce the symptoms of Parkinson's disease. This medicine is used as monotherapy (without L-dopamine) or as adjunctive therapy (in combination with L-dopamine) for the treatment of idiopathic Parkinson's disease. [0003] [0004] R...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/50C07C209/00C07C211/42C07C303/32C07C309/04
CPCC07C209/00C07C209/50C07C231/02C07C303/32C07C2602/08C07C211/42C07C233/09C07C309/04
Inventor 陈健于冲冲应述欢
Owner 上海新礼泰药业有限公司
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