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Improved process for preparing 2,3-dihydro-1H-indenes-1-amine and derivative thereof

A dihydrogen, hydroxylamine technology, applied in the preparation of amino-substituted functional groups, preparation through nitrogen-oxygen/nitrogen-nitrogen bonds, organic chemistry, etc., can solve the limitations of industrialization, high cost, and the difficulty of resolving agents. And other issues

Inactive Publication Date: 2007-10-31
CHONGQING PHARMA RES INST +1
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Problems solved by technology

[0004] 2,3-dihydro-1H-indene-1-amine (also known as 1-aminoindane, structure as shown in formula II) is an important intermediate for the preparation of rasagiline, the current literature reports 2,3-di The preparation method of hydrogen-1H-inden-1-amine (II) is basically through 2,3-dihydro-1H-inden-1-one oxime (also known as 1-indanone oxime, structure as shown in formula III ) reduction, the reduction method used has a higher cost in industrial production
[0005] There are two main types of prior art for preparing rasagiline (I) or its salts from 2,3-dihydro-1H-inden-1-amine (II), one is to first prepare 2,3-dihydro- 1H-inden-1-amine (II) is resolved to obtain (1R)-2,3-dihydro-1H-inden-1-amine, and then reacted with 3-substituted propyne (IV) to obtain N-alkylation reaction Sagiline (I), as disclosed in EP235590, uses D-N-acetyl-3,4-dimethoxyphenylalanine or L-(-)-N-acetylleucine to resolve 2,3-di Hydrogen-1H-inden-1-amine (II) obtains (1R)-2,3-dihydro-1H-inden-1-amine; CN1062900 and CN1191481 disclose (1R)-2,3-dihydro-1H- Inden-1-amine reacts with propargyl chloride, propargyl bromide or propargyl benzenesulfonate to obtain rasagiline (I). The method has mild reaction conditions and is easy to operate, but the used resolving agent is not easy The effect of obtaining or splitting is poor, which limits the realization of industrialization

Method used

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  • Improved process for preparing 2,3-dihydro-1H-indenes-1-amine and derivative thereof
  • Improved process for preparing 2,3-dihydro-1H-indenes-1-amine and derivative thereof
  • Improved process for preparing 2,3-dihydro-1H-indenes-1-amine and derivative thereof

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Experimental program
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Effect test

Embodiment 1

[0085] Preparation of 2,3-dihydro-1H-inden-1-amine (II)

[0086] In a 150ml three-necked flask, add 4.0g (27.2mmol) of 2,3-dihydro-1H-inden-1-one oxime (III), 40ml of ethanol, and 40ml of 20% sodium hydroxide solution, and control the temperature at 50-55°C , add aluminum-nickel alloy (nickel mass content 40-50%, 60-80 order) 6.0g in batches in 2~3 hours, react about 9 hours (TLC monitors reaction process, developer: normal hexane: ethyl acetate= 4:1). Filter, evaporate most of the ethanol in the filtrate under reduced pressure, extract with dichloromethane 30ml×3, combine the dichloromethane layers, wash with water and saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate to obtain the title compound (II) 2.9 g, oil.

[0087] IR (KBr): 3356, 3285, 3068, 3021, 2946, 2852, 1588, 1476, 1456, 1374, 1297, 1156, 1022, 951, 809, 758, 601, 459cm -1

[0088] EI-MS: 133 (M + ), 132, 116, 117, 115, 133, 104, 65, 91, 77, 51.

Embodiment 2

[0090] "One-pot" preparation of 2,3-dihydro-1H-inden-1-amine (II)

[0091]In a 10L reaction flask, add 890ml of water, 368.0g (5.296mol) of hydroxylamine hydrochloride, 890ml of ethanol and 350.0g (2.648mol) of 2,3-dihydro-1H-inden-1-one (VI), stir, and then add 1100ml of 20% sodium hydroxide solution; after the dropwise addition, heat and reflux for 30 minutes (TLC monitors the reaction process, developer: n-hexane: ethyl acetate = 4: 1); cool to 50°C, then add 1800ml of ethanol, 45 % sodium hydroxide solution 1100ml; control the internal temperature of the reaction system at 50-55°C, add 500g of aluminum-nickel alloy (nickel mass content 40-50%, 60-80 mesh) in batches within 2-3 hours; after adding, The reaction was continued at 50-55° C. for about 8 hours (TLC monitored the progress of the reaction, developing solvent: n-hexane: ethyl acetate = 4:1). Filter, extract the filtrate with dichloromethane 2L×3, combine the dichloromethane layers, wash with water until neutral; c...

Embodiment 3

[0093] Preparation of 2,3-dihydro-N-2-propynyl-1H-inden-1-amine (V)

[0094] In a 5L three-necked flask, add 2,3-dihydro-1H-inden-1-amine (II) hydrochloride 340.0g (2.004mol), water 600ml, 20% sodium hydroxide solution 700ml and toluene 800ml; Add 393.0 g (2.003 mol) of propargyl benzenesulfonate dropwise at ~25°C for about 70 minutes; Process, developer: n-hexane:ethyl acetate=4:1). After the reaction, cool to room temperature, separate the toluene layer, wash with 10% sodium hydroxide solution; add 550ml of water to the toluene layer, adjust the pH of the water layer to about 3 with 30% sulfuric acid solution; separate the water layer after extracting the toluene layer , adjust the pH with 10% sodium hydroxide solution to be about 8, extract the aqueous layer with 400ml×3 toluene; combine the toluene layers, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound (V) 271.3g, brown oil , HPLC: 93.08%.

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Abstract

The invention discloses an improved preparing method of anti-parkinson medicine detonate sand java blue important intermediate 2, 3- di-hydrogen- 1H-indenes-1-amine, which is characterized by the following: reacting 2, 3- di-hydrogen- 1H-indenes-1-ketoximes and alumino-nickel in queous alkali getting the product. This invention also discloses a 'one pot boiling' preparing method of 2, 3- di-hydrogen- 1H-indenes-1-amine with 2, 3- di-hydrogen- 1H-indenes-1- ketone. This invention also discloses a 'two steps one pot boiling' preparing method and 'three steps one pot boiling' preparing method of detonate sand java blue with 2, 3- di-hydrogen- 1H-indenes-1-ketoxime and 2, 3- di-hydrogen- 1H-indenes-1- ketone. This invention possesses simple operation, low cost and high productive efficiency, which is fit for industrial production.

Description

technical field [0001] The invention relates to the fields of synthetic organic chemistry and pharmacy, in particular to an improved method for preparing 2,3-dihydro-1H-inden-1-amine and its derivatives, which uses an aluminum-nickel alloy to reduce 2,3 under alkaline conditions -Dihydro-1H-inden-1-one oxime derived. 2,3-Dihydro-1H-inden-1-amine is an intermediate for the preparation of the anti-Parkinson drug rasagiline, and its derivative is (1R)-2,3-dihydro-N-2-propynyl -1H-inden-1-amine, also known as rasagiline. Background technique [0002] Rasagiline (Rasagiline), chemical name (1R)-2,3-dihydro-N-2-propynyl-1H-inden-1-amine, structure as shown in formula I, is an irreversible monoamine oxidase B The (MAO-B) selective inhibitor has dual effects of increasing dopamine levels and protecting nerves, and can better overcome the serious complications of current drugs for treating Parkinson's disease. Currently, rasagiline has been marketed in the EU and Israel in the for...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/40C07C209/04C07C211/42
Inventor 罗杰何伟叶文润林波
Owner CHONGQING PHARMA RES INST
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