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Preparation method of (R)-(+)-N-propargyl-1-indan amines

A technology of propargyl and indene amine, which is applied in the new preparation field of (R)-(+)-N-propargyl-1-indene amine, can solve the problem of different properties of 1-chloroindene or 1-bromoindene. Stability, not easy to industrialize production, serious side reaction of imine, etc

Inactive Publication Date: 2009-03-11
成都和康药业有限责任公司
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AI Technical Summary

Problems solved by technology

[0006] The shortcoming of this synthetic technique is: in addition to generating the desired secondary amine of propargyl monosubstituted on the nitrogen of 1-indenamine, simultaneously generate disubstituted tertiary amine and trisubstituted quaternary ammonium salt, which affects the reaction yield
[0012] In method 1, 1-chloroindene or 1-bromoindene is unstable in nature and prone to self-elimination reaction; in method 2, the side reaction of imine generation is serious, and it is not easy to industrialized production

Method used

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  • Preparation method of (R)-(+)-N-propargyl-1-indan amines

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Experimental program
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Embodiment 1

[0033] The preparation of compound (R)-N-(2-nitro)benzenesulfonyl-1-indenamine (III):

[0034] (R)-1-Indenamine 0.61g (4.59mmol) was dissolved in 10mL of dichloromethane, triethylamine 0.76mL (5.51mmol) was added, and o-nitrobenzenesulfonyl chloride 1.12g (5.05mmol) was added dropwise under ice cooling Dichloromethane (20mL) solution, reacted at 0°C for 4 hours, added 30mL of water, separated the dichloromethane layer, washed with saturated NaCl 30mL×2, dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure to obtain a white solid (III) 1.39 g, yield: 95%.

[0035] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 8.25 (m, 1H), 7.90 (m, 1H), 7.78 (m, 2H), 7.24 (m, 2H), 7.17 (m, 2H), 5.58 (d, J=8.4Hz, 1H , NH), 5.03(m, 1H, NCH), 2.95(m, 1H), 2.79(m, 1H), 2.35(m, 1H), 1.85(m, 1H); 13 C NMR (100MHz, CDCl 3 )δ (ppm) 142.8, 141.2, 133.6, 132.9, 130.8, 128.5, 127.0, 125.4, 124.9, 124.0, 59.6, 34.3, 30.0; ESI-MS, m / z: 318.4 [M] + , 336.1[M+H 2 O] + , 450.2[M+MeOH] ...

Embodiment 2

[0037] Preparation of compound (R)-N-propargyl-N-(2-nitro)benzenesulfonyl-1-indenamine (IV):

[0038] Dissolve 318 mg (1 mmol) of the above-mentioned white solid (III) in 10 mL of toluene, add 2.5 mL of aqueous sodium hydroxide solution (1 M) and a catalytic amount of tetrabutylammonium bromide (TBAB), then add 0.18 mL of propargyl bromide dropwise ( 2mmol) diluent of toluene (2mL), reacted at 70°C overnight, added 20mL of water and 20mL of ethyl acetate to the reaction solution, separated the organic layer, washed with saturated NaCl 30mL×2, dried over anhydrous sodium sulfate, evaporated under reduced pressure The solvent was removed, and the obtained oil was recrystallized from petroleum ether / ethyl acetate to obtain 287 mg of light yellow solid (IV), yield: 81%.

[0039] 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.24 (d, J = 4.8Hz, 1H), 7.72 (m, 3H), 7.25 (m, 2H), 7.17 (m, 2H), 5.62 (t, J = 8.0Hz, 1H, NCH ), 4.23 (d, J=18.4Hz, 1H, NCH 2 ), 3.62 (d, J=18.8Hz, 1H, NCH 2 ), 3.07...

Embodiment 3

[0041] The preparation of compound (R)-N-propargyl-1-indenamine (rasagiline) (I):

[0042] Dissolve 202 mg (0.57 mmol) of the above light yellow solid in 2 mL N,N-dimethylformamide, add 144 mg (3.43 mmol) of lithium hydroxide monohydrate and 60 μL (0.68 mmol) of mercaptopropionic acid under ice-cooling, and react at 0°C for 3 After 1 hour, 10 mL of water and 20 mL of ethyl acetate were added to the reaction solution, and the organic layer was separated, washed successively with 10 mL of water × 3, and 20 mL of saturated NaCl × 2, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain a yellow oil (I). 94 mg, yield: 96%.

[0043] 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.34 (d, J = 7.2Hz, 1H, ArH), 7.21 (m, 3H, ArH), 4.40 (t, J = 6.4Hz, 1H, NCH), 3.51 (t, J = 2.8Hz , 2H, NCH 2 ), 3.03(m, 1H), 2.82(m, 1H), 2.39(m, 1H), 2.25(t, J=2.4Hz, 1H, C≡C-H), 1.85(m, 1H); 13 C NMR (100MHz, CDCl 3 )δ (ppm) 144.4, 143.7, 127.5, 126.1, 124.8,...

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Abstract

The invention discloses a method for preparing rasagiline which has simple and convenient operation and is suitable for industrialized production. In the method, primary amine group on 1-indan amine is protected by o-Nos, and the 1-indan amine removes the protecting group after the 1-indan amine is substituted by propargyl chloride (or propargyl bromide); compared with the prior method, two steps of reactions are added in the method, but after the 1-indan amine is protected by the o-Nos, the reaction specificity of the 1-indan amine and the propargyl chloride (or the propargyl bromide) is greatly improved; and the protecting group can be easily removed after reaction without other side effects, so a single product is generated. Besides, raw materials and reaction reagent used in the method is cheap and easily obtained. The method has the advantages of simple and easy operation, mild reaction condition, easy control, good reaction selectivity, total yield improvement and cost reduction, and has excellent industrialized prospect.

Description

technical field [0001] The present invention relates to a new preparation method of (R)-(+)-N-propargyl-1-indenamine. Background technique [0002] (R)-(+)-N-propargyl-1-indenamine is jointly developed by Lundbeck Company and Teva Company, and is used as a drug for single or auxiliary levodopa treatment of Parkinson's disease. One of the main features of the pathological changes in Parkinson's disease is the degeneration of dopaminergic neurons, resulting in insufficient release of dopamine. (R)-(+)-N-propargyl-1-indenamine, as an irreversible and selective monoamine oxidase-B (MAO-B) inhibitor, can enhance the transduction signal of dopamine and block the decomposition of dopamine in the brain , while increasing extracellular levels of dopamine in the striatum, elevated dopamine levels and subsequent dopaminergic activity can regulate dopaminergic motor dysfunction. In addition, unlike other anti-Parkinson's disease drugs, the drug also has neuroprotective effects. (R)-(...

Claims

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Application Information

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IPC IPC(8): C07C211/42C07C209/08C07B53/00
CPCY02P20/55
Inventor 罗前东徐建张勇
Owner 成都和康药业有限责任公司
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