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Improved preparation method of rasagiline racemic intermediate

A technology of amine racemate and indanone, applied in the field of medicinal chemistry, can solve the problems of many by-products, low yield, heavy reaction color, etc., and achieve the effects of simple operation, low cost, and excellent product color state.

Active Publication Date: 2020-02-11
QILU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The present invention aims at the disadvantages of the existing synthetic method for preparing rasagiline by reductive amination method, such as low yield, many by-products, heavy reaction color, etc., and provides a kind of simple and convenient operation, environment-friendly, excellent color state of the product, The preparation method of rasagiline and its intermediates suitable for industrial production, especially fully reflected in cost and yield

Method used

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  • Improved preparation method of rasagiline racemic intermediate
  • Improved preparation method of rasagiline racemic intermediate
  • Improved preparation method of rasagiline racemic intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1 Preparation of N-(2-propargyl)-2,3-dihydro-1H-inden-1-amine racemate:

[0046] In a 3000ml three-necked flask, add 43.1g (1.139mol) of sodium borohydride and 560ml of tetrahydrofuran, suspend and stir. Add 209.9g (3.495mol) of glacial acetic acid and stir for 0.5 to 2 hours. After the reaction is complete, add 70.0g (0.530mol) of 1-indanone and continue to stir for reaction. Add 46.7g (0.848mol) propargylamine, then add 180.6g (0.635mol) tetraisopropyl titanate, control the reaction temperature not to exceed 50°C, stir the reaction for about 8 hours, and stop the reaction. Add 1400ml of 20% potassium carbonate solution to quench, extract twice with ethyl acetate, extract the organic phase twice with dilute hydrochloric acid, adjust the pH value to 11 with 20% sodium hydroxide, extract twice with ethyl acetate, and combine the organic phases , washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, ...

Embodiment 2

[0047] Example 2 Preparation of R-(+)-N-(2-propargyl)-2,3-dihydro-1H-indene-1-amine-L-(+)-tartrate

[0048] In a 3000ml three-necked flask, add 83.9g (0.490mol) of N-(2-propargyl)-2,3-dihydro-1H-inden-1-amine racemate prepared by the method in Example 1, add 1259ml of isopropanol was dissolved. Add 21.0g (0.140mol) L-(+)-tartaric acid to a 1000ml single-necked bottle, add 839ml of isopropanol to dissolve, and after both reaction bottles are dissolved, add the isopropanol of L-(+)-tartaric acid The solution was added dropwise to a solution of N-(2-propargyl)-2,3-dihydro-1H-indene-1-amine racemate in isopropanol. After the dropwise addition, the temperature was raised to reflux for 1.5 hours, cooled to room temperature, filtered by suction, and dried in vacuum to obtain 47.0 g of off-white solid with a yield of 39.0%. HPLC purity 99.46%, optical purity 95.54%.

Embodiment 3

[0049] The preparation of embodiment 3 rasagiline mesylate:

[0050] In a 2000ml three-necked flask, add 46.0g (0.187mol) of R-(+)-N-(2-propargyl)-2,3-dihydro-1H-indene-1- Amine-L-(+)-tartrate, add 500ml of purified water to dissolve. Adjust the pH value to about 10 with 20% potassium carbonate solution, extract twice with ethyl acetate, combine the organic phases, wash once with water and once with saturated brine, dry over anhydrous sodium sulfate, filter with suction, and evaporate to dryness under reduced pressure. Transfer to a 1000ml three-necked flask, add 230ml of isopropanol to dissolve, and dropwise add 23.3g (0.242mol) of methanesulfonic acid. After the dropwise addition, stir at room temperature for 1.5 hours, filter with suction, and dry in vacuo to obtain 43.8 g of off-white solid with a yield of 87.6%. HPLC purity 99.80%, maximum simple impurity 0.06%; optical purity 99.80%.

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Abstract

The invention discloses an improved preparation method of a rasagiline racemic intermediate, belongs to the technical field of medicinal chemistry, and particularly relates to an improved method for preparing an N-(2-propargyl)-2,3-dihydro-1H-indene-1-amine racemic body. According to the invention, the N-(2-propargyl)-2,3-dihydro-1H-indene-1-amine racemic body is prepared by using 1-indanone and propargylamine as raw materials through a one-pot method in the presence of a dehydrating agent; and the method is simple to operate, high in yield and good in purity, and establishes a good foundationfor subsequent preparation of rasagiline mesylate.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to an improved method for preparing N-(2-propargyl)-2,3-dihydro-1H-indene-1-amine racemate. The method uses 1-indanone and propargylamine as raw materials to prepare N-(2-propargyl)-2,3-dihydro-1H-inden-1-amine racemate in a "one-pot method". Simple, high yield, good product purity advantages. Background technique [0002] Rasagiline Mesylate, the chemical name is (R)-N-(2-propargyl)-2,3-dihydro-1H-indene-1-amine mesylate. Rasagiline mesylate is a selective monoamine oxidase B (MAO-B) inhibitor developed by Teva Company and Lundbeck Company, which can efficiently, selectively and irreversibly inhibit MAO-B. It has good chemical stability, It is convenient to use, less side effects, stronger effect and safer. It was launched in Israel for the first time in March 2005, and has been marketed in the UK, Ireland and China. The trade name is Azilect, which is ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/28C07C211/42
CPCC07C209/28C07C2602/08C07C211/42
Inventor 李建超高永宏孙崇振范传文
Owner QILU PHARMA CO LTD
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