CN101260048A - Method for preparing rasagiline - Google Patents
Method for preparing rasagiline Download PDFInfo
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- CN101260048A CN101260048A CNA2008100236199A CN200810023619A CN101260048A CN 101260048 A CN101260048 A CN 101260048A CN A2008100236199 A CNA2008100236199 A CN A2008100236199A CN 200810023619 A CN200810023619 A CN 200810023619A CN 101260048 A CN101260048 A CN 101260048A
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Abstract
The invention discloses a preparation method for rasagiline. The steps of the method is as follows: firstly 1-indone is taken as starting materials, and added in with chiral auxiliary reagents and reacted in solvents, obtaining compounds(II); secondly, under a certain condition, compounds(II) obtained are reduced in proper solvents for obtaining compounds(III); thirdly, under a certain temperature and in a certain solvent, compounds(III) obtained undergo the actions of alkali and acid for obtaining compounds(IV); fourthly, under a certain temperature and in a certain solvent, compounds(IV) obtained are filled with HCI gases, obtaining compounds(V); fifthly under a certain temperature and in a certain solvent, compounds(V) obtained react with 3- propargyl bromide under the action of alkali so as to obtain compounds(VI); finally, under a certain temperature and in a certain solvent, compounds(VI) obtained are dropwise added with methanesulfonic acid to obtain the rasagiline(VII). The method of the invention has the advantages of simple operation, low cost, high yield and little pollution, and is suitable for the industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of rasagiline, relate in particular to a kind of preparation method who is used for Mirapexin thing rasagiline.
Background technology
Rasagiline (rasagiline) is a kind of Mirapexin thing.It is the Irreversible selective oxidase inhibitor, belong to the irreversible monoamine oxidase beta inhibitor of the s-generation, compare with previous propargyl amine monoamine oxidase beta inhibitor (as selegiline), it is strong to have effect, can not produce the advantages such as metabolite of amphetamine.In addition by board of consultants of European medicine assessment administration as early stage Parkinsonian's initial single medical service law and in to severe patient's adjuvant therapy, can significantly improve motor symptom and quality of life, can also significantly reduce the illness motion anergy in late period, compare with other treatment Parkinson's disease medicine, the incidence of its toxic side effect is lower.In addition, this medicine is at present also in the clinical study that is used for the treatment of senile dementia (A D), dysthymia disorders, childhood hyperkinetic syndrome.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of rasagiline, this method has advantages such as easy and simple to handle, that cost is lower, yield is higher, pollution is less, is suitable for the suitability for industrialized production needs more.
Technical scheme of the present invention is: the preparation method of a kind of rasagiline (R)-N-2-Propynyl-1-indanaminemethanesulfonate may further comprise the steps:
(1) with the 1-indone
Be starting raw material, under 50-150 ℃ temperature condition, introduce chiral auxiliary(reagent), reaction obtains compound (II) in suitable solvent; Described solvent comprises at least a in the following material: ethyl acetate, methyl alcohol, ethanol, benzene, toluene, isopropyl acetate, isobutyl acetate;
(2) with the compound (II) that obtains in the step (1), under temperature 0-50 ℃, pressure 0-50atm condition, reduction obtains compound (III) in suitable solvent; Described suitable solvent comprises at least a in the following material: ethyl acetate, methyl alcohol, ethanol, benzene, toluene;
(3), under 50-100 ℃ of temperature condition and in the suitable solvent, under the effect of alkali and acid, obtain compound (IV) with the compound (III) that obtains in the step (2); Described suitable solvent comprises at least a in the following material: ethyl acetate, methyl alcohol, ethanol, benzene, toluene, tetrahydrofuran (THF);
(4) with the compound (IV) that obtains in the step (3), under-20-20 ℃ temperature condition and in the suitable solvent, feed HCl gas, obtain compound (V); Described suitable solvent comprises at least a in the following material: ethyl acetate, methylene dichloride, chloroform, normal hexane;
(5), under 0-30 ℃ of temperature condition and in the suitable solvent, under the effect of alkali, obtain compound (VI) with the reaction of 3-propargyl bromide with the compound (V) that obtains in the step (4); Described suitable solvent comprises at least a in the following material: methylene dichloride, ethyl acetate, methyl alcohol, ethanol, tetrahydrofuran (THF), acetonitrile;
(6), under 0-50 ℃ of temperature condition, and in the suitable solvent, drip methanesulfonic and obtain rasagiline (VII) with the compound (VI) that obtains in the step (5); Described suitable solvent comprises at least a in the following material: ethyl acetate, methyl alcohol, ethanol, ether, isopropyl ether.
The further technical scheme of the present invention is: a kind of preparation method of rasagiline, and described rasagiline is the Chiral Amine compounds with following structure formation:
May further comprise the steps:
(1) with the 1-indone
Be starting raw material, under 50-150 ℃ temperature condition, best 80-120 ℃, introduce chiral auxiliary(reagent), reaction obtains compound (II) in suitable solvent; Described solvent comprises at least a in the following material: ethyl acetate, methyl alcohol, ethanol, benzene, toluene, isopropyl acetate, isobutyl acetate; Described chiral auxiliary(reagent) comprises at least a in the following material: chiral amino acid, chiral amino alcohol, the glycol of chirality, the acid amides of chirality, the amine of chirality, the carboxylic acid of chirality;
(2) with the compound (II) that obtains in the step (1), under temperature 0-50 ℃, pressure 0-50atm condition, optimum temperature range 0-30 ℃, pressure range 1-10atm; Reduction obtains compound (III) in suitable solvent; Described suitable solvent comprises at least a in the following material: ethyl acetate, methyl alcohol, ethanol, benzene, toluene;
(3), under 50-100 ℃ of temperature condition and in the suitable solvent, under the effect of alkali and acid, obtain compound (IV) with the compound (III) that obtains in the step (2); Described suitable solvent comprises at least a in the following material: ethyl acetate, methyl alcohol, ethanol, benzene, toluene, tetrahydrofuran (THF); Described alkali can be mineral alkali, also can be organic bases, or both are with a certain proportion of combination, and it can comprise at least a in the following material: sodium hydroxide, yellow soda ash, sodium bicarbonate, triethylamine; Described acid comprises at least a in the following material: hydrochloric acid, phosphorus trichloride;
(4) with the compound (IV) that obtains in the step (3), under-20-20 ℃ temperature condition and in the suitable solvent, feed HCl gas, obtain compound (V); Described suitable solvent comprises at least a in the following material: ethyl acetate, methylene dichloride, chloroform, normal hexane;
(5) with the compound (V) that obtains in the step (4), under 0-30 ℃ of temperature condition, best 20-30 ℃, and in the suitable solvent, under the effect of alkali, obtain compound (VI) with the reaction of 3-propargyl bromide; Described suitable solvent comprises at least a in the following material: methylene dichloride, ethyl acetate, methyl alcohol, ethanol, tetrahydrofuran (THF), acetonitrile; Described alkali comprises at least a in the following material: sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, triethylamine;
(6) with the compound (VI) that obtains in the step (5), under 0-50 ℃ of temperature condition, best 20-30 ℃, and in the suitable solvent, drip methanesulfonic and obtain rasagiline (VII); Described suitable solvent comprises at least a in the following material: ethyl acetate, methyl alcohol, ethanol, ether, isopropyl ether.
The synthetic route of rasagiline of the present invention (VII) is as follows:
Specifically be divided into:
Advantage of the present invention is:
1. synthesis technique of the present invention is selected rationally, and is simple to operate, need not to carry out complicated fractionation and purifying, reduced production cost.
2. raw material sources of the present invention are convenient, and the chemical yield height of product, optical purity height pollute lessly, are suitable for suitability for industrialized production.
Embodiment
Below in conjunction with embodiment the present invention is further described:
Embodiment:
1. the preparation of compound (II)
In the 100mL round-bottomed flask, add (S)-phenylethylamine (8.24g, 0.068mol), the 1-indone (9.79g, 1.1equiv), one hydration tosic acid (0.65g, 5mol%), the 50mL isopropyl acetate installs water-and-oil separator, backflow 6h, be cooled to room temperature, continue to stir 3h, filter and obtain white solid; Then the solid that obtains is dissolved in the 50mL water and stirs 5min, filter, use 15mL water, 15mL * 2 isopropyl acetates washing successively, obtain compound (II) 13.2g, productive rate 82.5%.
2. the preparation of compound (III)
Add compound (II) (13.2g in the 1L autoclave, 0.056mol), 200mL isopropyl acetate, 15g (125w/w%) Raney's nickel (using 50mL * 2 methyl alcohol, 50mL * 2 isopropyl acetate washed twice successively), at 3.5bar H2,40 ℃ of reaction 45h, filter, and with 300mL isopropyl acetate washing filter residue, obtain compound (III) 11.71g, productive rate 88% after concentrating the removal solvent.
3. the preparation of compound (IV)
Add (4.94g, 0.0208mol) compound (III), 75mL THF, the Et of 35mL (12equiv) in the 250mL round-bottomed flask
3N, put then with ice-water bath in be chilled to 0 ℃, drip (5.5mL, 2.2equiv) PCl
5, add the back and continue under ice bath, to stir 15min, stir 1h under the room temperature, the 5h that refluxes then is cooled to room temperature, adds NH
2The aqueous solution of OHHCl (4.34g NH
2OHHCl, 3equiv is dissolved in the 75mL water), continue to stir 16h under the room temperature, concentrate and remove THF, drip 30% hydrochloric acid conditioning solution pH=1 (needing 20mL approximately), (2 * 75mL) washed twice add 100mLCH then with methyl tertiary butyl ether
2Cl
2, regulate pH=9 (needing 25mL approximately) with 33%NaOH solution, tell CH
2Cl
2Layer, anhydrous sodium sulfate drying obtains compound (IV) 1.94g, productive rate 70% after concentrating.
4. the preparation of compound (V)
Add in the 250mL round-bottomed flask (1.94g, 0.0146mol) compound (IV) add the 100mL ethyl acetate, put then with ice-water bath in be chilled to 0 ℃, feed HCl gas, filter and obtain compound (V) 2.43g, productive rate 98%.
5. the preparation of compound (VI) and compound (VII)
In the three-necked flask of a 2L; hydrochloride (compound (V)) (20g that adds the amino indenes of 1-; 117.89mmol); salt of wormwood (32.59g; 235.78mmol) and the acetonitrile of 800mL, be heated to 60 ℃ under the nitrogen protection and refluxed 2 hours, behind the cool to room temperature; slowly drip acetonitrile (100mL) solution of 3-propargyl bromide (18.02g), about 20min drips off.After the system stirring at room 24 hours, filter, filtrate evaporate to dryness, residuum join in 400mL water and the 400mL toluene, and the hydrochloric acid with 20% is regulated PH=4.Separatory, water afterwards, is removed toluene layer with toluene extraction (200mL * 3).Water is regulated PH=8 with 10% sodium hydroxide, and with toluene extraction (200mL * 5), combining methylbenzene layer, anhydrous sodium sulfate drying concentrates and obtains flaxen liquid, and compound (VI) (13.1g).In this liquid, add anhydrous diethyl ether 600mL, slowly drip the anhydrous ether solution (8.2g of methanesulfonic under the churned mechanically situation, 100mL) anhydrous diethyl ether, about 30min drips off, and continues to stir the 2h after-filtration, and filter cake washs with anhydrous diethyl ether, obtain the white solid crude product, purify through the Virahol recrystallization, obtain compound (VII) 20.04g, productive rate 63.6%.
mp：156-158℃，[α]20D＝+22.5°(c＝1，C
2H
5OH)。
Easy and simple to handle, the advantages such as cost is lower, yield is higher, less pollution that the inventive method has, more Be suitable for the suitability for industrialized production needs.
Claims (8)
1. the preparation method of a rasagiline is characterized in that may further comprise the steps:
(1) with the 1-indone
Be starting raw material, under 50-150 ℃ temperature condition, introduce chiral auxiliary(reagent), reaction obtains compound (II) in suitable solvent; Described solvent comprises at least a in the following material: ethyl acetate, methyl alcohol, ethanol, benzene, toluene, isopropyl acetate, isobutyl acetate;
(2) with the compound (II) that obtains in the step (1), under temperature 0-50 ℃, pressure 0-50atm condition, reduction obtains compound (III) in suitable solvent; Described suitable solvent comprises at least a in the following material: ethyl acetate, methyl alcohol, ethanol, benzene, toluene, tetrahydrofuran (THF);
(3), under 50-100 ℃ of temperature condition and in the suitable solvent, under the effect of alkali and acid, obtain compound (IV) with the compound (III) that obtains in the step (2); Described suitable solvent comprises at least a in the following material: ethyl acetate, methyl alcohol, ethanol, benzene, toluene, tetrahydrofuran (THF);
(4) with the compound (IV) that obtains in the step (3), under-20-20 ℃ temperature condition and in the suitable solvent, feed HCl gas, obtain compound (V); Described suitable solvent comprises at least a in the following material: ethyl acetate, methylene dichloride, chloroform, normal hexane;
(5), under 0-30 ℃ of temperature condition and in the suitable solvent, under the effect of alkali, obtain compound (VI) with the reaction of 3-propargyl bromide with the compound (V) that obtains in the step (4); Described suitable solvent comprises at least a in the following material: methylene dichloride, ethyl acetate, methyl alcohol, ethanol, tetrahydrofuran (THF), acetonitrile;
(6), under 0-50 ℃ of temperature condition and in the suitable solvent, drip methanesulfonic and obtain rasagiline (VII) with the compound (VI) that obtains in the step (5); Described suitable solvent comprises at least a in the following material: ethyl acetate, methyl alcohol, ethanol, ether, isopropyl ether.
2. according to the preparation method of the described rasagiline of claim 1, it is characterized in that: chiral auxiliary(reagent) described in the step (1) comprises at least a in the following material: chiral amino acid, chiral amino alcohol, the glycol of chirality, the acid amides of chirality, the amine of chirality, the carboxylic acid of chirality.
3. according to the preparation method of the described rasagiline of claim 1, it is characterized in that: being reflected under the 80-120 ℃ of temperature condition in the step (1) carried out.
4. according to the preparation method of the described rasagiline of claim 1, it is characterized in that: be reflected at temperature range 0-30 ℃ in the step (2), carry out under the pressure range 1-10atm.
5. according to the preparation method of the described rasagiline of claim 1, it is characterized in that: the alkali described in the step (3) comprises at least a in the following material: sodium hydroxide, yellow soda ash, sodium bicarbonate, triethylamine; Described acid comprises at least a in the following material: hydrochloric acid, phosphorus trichloride.
6. according to the preparation method of the described rasagiline of claim 1, it is characterized in that: being reflected under the 20-30 ℃ of temperature condition in the step (5) carried out.
7. according to the preparation method of the described rasagiline of claim 1, it is characterized in that: the alkali described in the step (5) comprises at least a in the following material: sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, triethylamine.
8. according to the preparation method of the described rasagiline of claim 1, it is characterized in that: being reflected under the 20-30 ℃ of temperature condition in the step (6) carried out.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100236199A CN101260048A (en) | 2008-04-15 | 2008-04-15 | Method for preparing rasagiline |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100236199A CN101260048A (en) | 2008-04-15 | 2008-04-15 | Method for preparing rasagiline |
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| CN101260048A true CN101260048A (en) | 2008-09-10 |
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| CNA2008100236199A Pending CN101260048A (en) | 2008-04-15 | 2008-04-15 | Method for preparing rasagiline |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009122301A3 (en) * | 2008-03-31 | 2009-11-26 | Actavis Group Ptc Ehf | Rasagiline mesylate particles and process for the preparation thereof |
| CN102010353A (en) * | 2010-10-22 | 2011-04-13 | 湖北能特科技股份有限公司 | New method for preparing rasagiline mesylate |
| WO2011048612A2 (en) * | 2009-10-14 | 2011-04-28 | Glenmark Generics Limited | Processes for the preparation of propargylated aminoindans or a pharmaceutically acceptable salt thereof |
| CN102154432A (en) * | 2010-12-20 | 2011-08-17 | 蚌埠丰原医药科技发展有限公司 | Method for preparing rasagiline |
| CN109180499A (en) * | 2018-07-31 | 2019-01-11 | 上海博志研新药物技术有限公司 | The preparation method of rasagiline mesilate and its intermediate |
| CN110229067A (en) * | 2019-06-05 | 2019-09-13 | 南京焕然生物科技有限公司 | A kind of 2- amino indenes preparation method |
| CN110615747A (en) * | 2018-06-20 | 2019-12-27 | 广东东阳光药业有限公司 | Preparation method of indane intermediate |
| CN111333517A (en) * | 2018-12-19 | 2020-06-26 | 上海奥博生物医药技术有限公司 | Improved method for preparing rasagiline |
-
2008
- 2008-04-15 CN CNA2008100236199A patent/CN101260048A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009122301A3 (en) * | 2008-03-31 | 2009-11-26 | Actavis Group Ptc Ehf | Rasagiline mesylate particles and process for the preparation thereof |
| WO2011048612A2 (en) * | 2009-10-14 | 2011-04-28 | Glenmark Generics Limited | Processes for the preparation of propargylated aminoindans or a pharmaceutically acceptable salt thereof |
| WO2011048612A3 (en) * | 2009-10-14 | 2011-08-11 | Glenmark Generics Limited | Process for preparation of propargylated aminoindans or pharmaceutically acceptable salts thereof |
| CN102010353A (en) * | 2010-10-22 | 2011-04-13 | 湖北能特科技股份有限公司 | New method for preparing rasagiline mesylate |
| CN102154432A (en) * | 2010-12-20 | 2011-08-17 | 蚌埠丰原医药科技发展有限公司 | Method for preparing rasagiline |
| CN102154432B (en) * | 2010-12-20 | 2013-06-12 | 蚌埠丰原医药科技发展有限公司 | Method for preparing rasagiline |
| CN110615747A (en) * | 2018-06-20 | 2019-12-27 | 广东东阳光药业有限公司 | Preparation method of indane intermediate |
| CN109180499A (en) * | 2018-07-31 | 2019-01-11 | 上海博志研新药物技术有限公司 | The preparation method of rasagiline mesilate and its intermediate |
| CN109180499B (en) * | 2018-07-31 | 2021-04-30 | 上海博志研新药物技术有限公司 | Preparation method of rasagiline mesylate and intermediate thereof |
| CN111333517A (en) * | 2018-12-19 | 2020-06-26 | 上海奥博生物医药技术有限公司 | Improved method for preparing rasagiline |
| CN110229067A (en) * | 2019-06-05 | 2019-09-13 | 南京焕然生物科技有限公司 | A kind of 2- amino indenes preparation method |
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