Method for preparing rasagiline

Abstract

The invention provides a method for preparing a compound rasagiline [(R)-N-propargyl-1-indanamine]. In the method, the rasagiline is prepared from (R,S)-1-indanamine serving as a raw material through enzyme-catalyzed asymmetric acylation reaction, hydrolysis and N propargylation reaction. The method for preparing the rasagiline provided by the invention has the advantages of readily available reaction raw material, high product yield and high optical purity and is suitable for industrial production.

Description

technical field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a compound rasagiline [(R)-N-propargyl-1-aminoindan, (R)-N-2-Propynyl-1-indanamine , the preparation method of Rasagiline]. Background technique

[0002] Rasagiline is (R)-N-propargyl-1-aminoindene, its structural formula is:

[0003]

[0004] Molecular formula: C 12 h 13 N

[0005] Molecular weight: 171.1

[0006] Rasagiline salts, such as rasagiline mesylate, are highly selective, irreversible monoamine oxidase-B (MAO-B) inhibitors that can be used as an adjunct to levodopa in Parkinson's disease The treatment of the drug, which was developed and produced by Israel's Teva Company, was approved for marketing in Europe in February 2005 and has been approved by the US FDA. Compared with similar drugs, the drug has small adverse reactions, high efficacy and good selectivity, and is a promising new drug for anti-Parkinson's disease. At present, although rasagili...

Examples

Embodiment 1

[0029] The preparation of embodiment 1 (R)-1-aminoindan

[0030] Dissolve 13.3g (100mmol) (R,S)-1-aminoindan and 17.6g (200mmol) ethyl acetate in 400ml n-hexane, then add 8g Novozym 435, and stir the reaction at room temperature for 24h. After the reaction, the immobilized enzyme was filtered out, 200 ml of distilled water was added to the filtrate, the pH was adjusted to 5.0 with 1.2 mol / L hydrochloric acid solution, and the liquid was separated. The organic layer was first washed with 100ml of saturated ammonium chloride solution, then washed with saturated sodium chloride solution to neutrality, added anhydrous magnesium sulfate to dry, evaporated to dryness under reduced pressure, and left overnight to obtain a flaky light yellow solid, which was (R )-amide of 1-aminoindane.

[0031] Dissolve the produced amide in 4.0 g of triethanolamine, add 8.0 g of 50% NaOH solution, heat to 120° C., and keep the reaction for 2 h. Cool the reaction compound to room temperature, add 2...

Embodiment 2

[0032] The preparation of embodiment 2 (R)-1-aminoindan

[0033] Dissolve 13.3g (100mmol) (R,S)-1-aminoindan and 8.3g (80mmol) methyl methoxyacetate in 400ml isopropyl ether, then add 7.0g Novozym 435, and stir the reaction at room temperature for 7h. After the reaction, the immobilized enzyme was filtered out, 200 ml of distilled water was added to the filtrate, the pH was adjusted to 5.0 with 1.2 mol / L hydrochloric acid solution, and the liquid was separated. The organic layer was first washed with 100ml of saturated ammonium chloride solution, then washed with saturated sodium chloride solution to neutrality, added anhydrous magnesium sulfate to dry, evaporated to dryness under reduced pressure, and left overnight to obtain a flaky light yellow solid, which was (R )-amide of 1-aminoindane.

[0034] Dissolve the produced amide in 4.0 g of triethanolamine, add 8.0 g of 50% NaOH solution, heat to 120° C., and keep the reaction for 6 h. Cool the reaction compound to room temp...

Embodiment 3

[0035] The preparation of embodiment 3 (R)-N-propargyl-1-aminoindan

[0036] Add 100ml isopropyl ether, 160ml 10% Na in the 500ml three-necked flask 2 CO 3 solution (with Na 2 CO 3 150mmol), at room temperature, add (R)-1-aminoindane 13.3g (100mmol) while stirring, and stir vigorously for 20min. Slowly add 22.5 g of propargyl benzenesulfonate (110 mmol) dropwise to the system, and rinse the dropping funnel with 20 ml of isopropyl ether after the dropwise addition. The temperature was raised to 60° C., and the reaction was kept for 7 hours.

[0037] Pour the reaction solution into a 1L separatory funnel, wash the container with 30ml of isopropyl ether, then pour into the separatory funnel, shake, let stand, and separate layers to obtain an organic phase (upper layer). The aqueous layer was extracted twice with isopropyl ether, 30 ml each time, and the organic phases were combined.

[0038] Add 1.2 mol / L hydrochloric acid to the organic phase and extract three times, respe...

technical field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a compound rasagiline [(R)-N-propargyl-1-aminoindan, (R)-N-2-Propynyl-1-indanamine , the preparation method of Rasagiline]. Background technique

[0002] Rasagiline is (R)-N-propargyl-1-aminoindene, its structural formula is:

[0003]

[0004] Molecular formula: C 12 h 13 N

[0005] Molecular weight: 171.1

[0006] Rasagiline salts, such as rasagiline mesylate, are highly selective, irreversible monoamine oxidase-B (MAO-B) inhibitors that can be used as an adjunct to levodopa in Parkinson's disease The treatment of the drug, which was developed and produced by Israel's Teva Company, was approved for marketing in Europe in February 2005 and has been approved by the US FDA. Compared with similar drugs, the drug has small adverse reactions, high efficacy and good selectivity, and is a promising new drug for anti-Parkinson's disease. At present, although rasagili...

Examples

Embodiment 1

[0029] The preparation of embodiment 1 (R)-1-aminoindan

[0030] Dissolve 13.3g (100mmol) (R,S)-1-aminoindan and 17.6g (200mmol) ethyl acetate in 400ml n-hexane, then add 8g Novozym 435, and stir the reaction at room temperature for 24h. After the reaction, the immobilized enzyme was filtered out, 200 ml of distilled water was added to the filtrate, the pH was adjusted to 5.0 with 1.2 mol / L hydrochloric acid solution, and the liquid was separated. The organic layer was first washed with 100ml of saturated ammonium chloride solution, then washed with saturated sodium chloride solution to neutrality, added anhydrous magnesium sulfate to dry, evaporated to dryness under reduced pressure, and left overnight to obtain a flaky light yellow solid, which was (R )-amide of 1-aminoindane.

[0031] Dissolve the produced amide in 4.0 g of triethanolamine, add 8.0 g of 50% NaOH solution, heat to 120° C., and keep the reaction for 2 h. Cool the reaction compound to room temperature, add 2...

Embodiment 2

[0032] The preparation of embodiment 2 (R)-1-aminoindan

[0033] Dissolve 13.3g (100mmol) (R,S)-1-aminoindan and 8.3g (80mmol) methyl methoxyacetate in 400ml isopropyl ether, then add 7.0g Novozym 435, and stir the reaction at room temperature for 7h. After the reaction, the immobilized enzyme was filtered out, 200 ml of distilled water was added to the filtrate, the pH was adjusted to 5.0 with 1.2 mol / L hydrochloric acid solution, and the liquid was separated. The organic layer was first washed with 100ml of saturated ammonium chloride solution, then washed with saturated sodium chloride solution to neutrality, added anhydrous magnesium sulfate to dry, evaporated to dryness under reduced pressure, and left overnight to obtain a flaky light yellow solid, which was (R )-amide of 1-aminoindane.

[0034] Dissolve the produced amide in 4.0 g of triethanolamine, add 8.0 g of 50% NaOH solution, heat to 120° C., and keep the reaction for 6 h. Cool the reaction compound to room temp...

Embodiment 3

[0035] The preparation of embodiment 3 (R)-N-propargyl-1-aminoindan

[0036] Add 100ml isopropyl ether, 160ml 10% Na in the 500ml three-necked flask 2 CO 3 solution (with Na 2 CO 3 150mmol), at room temperature, add (R)-1-aminoindane 13.3g (100mmol) while stirring, and stir vigorously for 20min. Slowly add 22.5 g of propargyl benzenesulfonate (110 mmol) dropwise to the system, and rinse the dropping funnel with 20 ml of isopropyl ether after the dropwise addition. The temperature was raised to 60° C., and the reaction was kept for 7 hours.

[0037] Pour the reaction solution into a 1L separatory funnel, wash the container with 30ml of isopropyl ether, then pour into the separatory funnel, shake, let stand, and separate layers to obtain an organic phase (upper layer). The aqueous layer was extracted twice with isopropyl ether, 30 ml each time, and the organic phases were combined.

[0038] Add 1.2 mol / L hydrochloric acid to the organic phase and extract three times, respe...

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