CN101891641A - Stable form of key intermediate of ropinirole hydrochloride and preparation thereof - Google Patents
Stable form of key intermediate of ropinirole hydrochloride and preparation thereof Download PDFInfo
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- CN101891641A CN101891641A CN2010102376622A CN201010237662A CN101891641A CN 101891641 A CN101891641 A CN 101891641A CN 2010102376622 A CN2010102376622 A CN 2010102376622A CN 201010237662 A CN201010237662 A CN 201010237662A CN 101891641 A CN101891641 A CN 101891641A
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Abstract
In the invention, the intermediate of ropinirole hydrochloride is converted into corresponding metal salts, thus a stable form of the intermediate and a preparation method thereof are provided.
Description
Technical field
The invention belongs to technical field of medicine synthesis, particularly the stable form and the preparation thereof of ropinirole hydrochloride key intermediate.
Background technology
Ropinirole hydrochloride is the non-ergot bases of a kind of potent selectivity dopamine D 2-receptor stimulant, can directly excite the striatum Dopamine Receptors, thereby improve bradykinesia, stiff and tremble and depressive emotion, improve Parkinsonian's activity of daily living, develop by Britain SmithKline Beecham company, in 1996 in Britain's Initial Public Offering.Soon, France, the U.S. also get permission listing, trade(brand)name Requip.Since listing, sales volume rises successively, and the global marketing volume was 8,000 ten thousand dollars in 2000, increases by 20%, 2003 year than 1999 and has reached 1.8 hundred million dollars, and annual growth rate is all more than 20%, the 3rd of the sales volume rank in the Mirapexin thing.These medicines in 2004 are used for the treatment of the restless leg syndrome (RLS) of moderate or severe again by the FDA approval, because of advantages such as its indication are wide, better tolerance, dosage are little, be subjected to people's attention.
One of chemical synthesis process of ropinirole hydrochloride is to be starting raw material with 2-methyl-3-nitro toluylic acid, through following synthetic route, obtains end product, and yield is higher, is about 23%.
The original synthetic route of ropinirole hydrochloride
This also is a synthetic route the earliest, the starting material synthetic hydrochloric acid Ropinirole of report with other arranged subsequently successively, but yield is generally on the low side, and exist much be not suitable for industrialized factor (Huang Lu etc. the synthesis progress of ropinirole hydrochloride. chemistry and biotechnology, 2008,4 (25)), this makes selects this synthetic route in the actual production still morely, and along with the manufacturing development of industrial chemicals, the price of raw material 2-methyl-3-nitro toluylic acid also begins to reduce, and has saved the cost of this synthetic method.
The key intermediate of this synthetic route (3), chemical name: { 2-nitro-6-[(2-N, N-di amino) ethyl] phenyl } Pyruvic Acid Ethyl ester, patent documentation has given different reports both at home and abroad, US4452808, WO2006123356, WO2008084499 etc. report and have affirmed the stable existence of this midbody compound successively, and (J.Med.Chem.1985,28 such as Robert M., 1523～1536, and 1986,29,939～947) then think this compound instability in the post-reaction treatment process, can generate 2-nitro-6-[(2-N, N-di amino) ethyl] phenyl pyruvic acid.Structural formula is as follows:
Domestic (Chinese Journal of Pharmaceuticals, 2007,38 (1)) such as Sun Pinghua have proposed identical view.We find that by actual R﹠D process post treatment acid basicity is difficult to hold in the prepared process of intermediate (3), and technology is extremely unstable, poor reproducibility.And the product loss is more in the last handling process of preparation intermediate (3-1), and yield only is 21.3～32.0%, does not reach the reported values 52%～79% of document far away.
For this reason, the contriver has carried out the exploration of intermediate (3) stable form synthetic method, a kind of yield height is provided, constant product quality, simple to operate, the method that suitability for industrialized is produced, and in this process, synthesized the stable form of intermediate (3) analogue, this compounds can be used for preparing the intermediate (2) of ropinirole hydrochloride.
Summary of the invention
The invention provides the stable form (V) of general formula (X) compound, can be used as the intermediate of preparation ropinirole hydrochloride, its chemical formula is as follows:
Wherein R is methyl or ethyl, and M is sodium Metal 99.5 or potassium metal.
The present invention also provides the method for the stable form (V) of a kind of preparation general formula (X) compound, and described method may further comprise the steps:
(a). metal M is suspended in the anhydrous aprotic solvent, adds anhydrous alcohol reagent to prepare the alkoxide of fresh metal M;
(b) in above-mentioned reaction solution, be added dropwise to N, N-di-2-methyl-3-nitro phenylethylamine, insulated and stirred 1-2 hour under .-20～-10 ℃;
(c) ℃ following dimethyl oxalate or oxalic acid diethyl ester, insulated and stirred 12-24 hour of dripping .-20～-10;
(d). filter, obtain the red solid precipitation, dry 5-15 hour, promptly get logical formula V compound.
Anhydrous aprotic solvent used in the preparation process of the present invention (a) is anhydrous tetrahydro furan and anhydrous diethyl ether, is preferably anhydrous tetrahydro furan.Metal M is sodium and potassium, is preferably potassium, and the alkoxide of its formation has better activity.Used anhydrous alcohol reagent is methyl alcohol and ethanol, when substituent R is methyl, is preferably methyl alcohol, when substituent R is ethyl, is preferably ethanol.
The present invention can make the preparation of ropinirole hydrochloride be prepared according to following route, shown in reaction formula is expressed as follows:
Through the ropinirole hydrochloride synthetic route behind the stable form intermediate
Contribution of the present invention has been to seek a class in order to stable form of the intermediate of producing ropinirole hydrochloride and preparation method thereof, makes that the route of synthetic hydrochloric acid Ropinirole is more reasonable, and yield is higher, simplified control, and quality product is more stable.
Embodiment
Embodiment (one)
The preparation of { 2-nitro-6-[(2-N, N-di amino) ethyl] phenyl } Pyruvic Acid Ethyl ester sylvite
The 500L there-necked flask, fully nitrogen protection is transferred cold behind the heat drying.0～5 ℃ adds anhydrous tetrahydro furan (definitely) 50ml down, adds the potassium metal of newly cutting (2.0g) under the nitrogen gas stream, drips dehydrated alcohol (3.0g), and a large amount of hydrogen produce.Treat that potassium metal dissolves substantially, in-20～-15 ℃ of dropping N, N-di-2-methyl-3-nitro phenylethylamine (13.2g), the reaction solution color becomes black, dropwises-20～-15 ℃ of following insulated and stirred 75 minutes.-20～-15 ℃ drip oxalic acid diethyl ester (7.3g).Reaction solution becomes dark reddish purple look.Insulated and stirred 24 hours has a large amount of solids to separate out.The TLC detection reaction is complete.Reacting liquid filtering obtains red solid, pulls an oar (50ml * 3) to bright red with anhydrous tetrahydro furan.Air is placed drying and is obtained { 2-nitro-6-[(2-N, N-di amino) ethyl] phenyl } Pyruvic Acid Ethyl ester sylvite 12.9g.TLC is shown as single-point (developping agent condition ethyl acetate: sherwood oil=2: 1, product R
f=0.3).Yield 64.2%.
Embodiment (two)
The preparation of { 2-nitro-6-[(2-N, N-di amino) ethyl] phenyl } Pyruvic Acid Ethyl ester sodium salt
The 500L there-necked flask, fully nitrogen protection is transferred cold behind the heat drying.Add anhydrous tetrahydro furan (definitely) 50ml under the room temperature, add the sodium Metal 99.5 of newly cutting (1.2g) under the nitrogen gas stream, drip dehydrated alcohol (3.0g), temperature rising reflux produces to no hydrogen and ends, be cooled to-25～-20 ℃, drip N, N-di-2-methyl-3-nitro phenylethylamine (13.2g), the reaction solution color becomes black, dropwises-25～-20 ℃ of following insulated and stirred 2 hours.-25～-20 ℃ drip oxalic acid diethyl ester (7.3g).Reaction solution becomes dark reddish purple look.Insulated and stirred 24 hours has a large amount of solids to separate out.The TLC detection reaction is complete.Reacting liquid filtering obtains red solid, pulls an oar (50ml * 3) to bright red with anhydrous tetrahydro furan.Air is placed drying and is obtained { 2-nitro-6-[(2-N, N-di amino) ethyl] phenyl } Pyruvic Acid Ethyl ester sodium salt 11.2g.TLC is shown as single-point (developping agent condition ethyl acetate: sherwood oil=2: 1, product R
f=0.3).Yield 58.0%.
Embodiment (three)
The preparation of { 2-nitro-6-[(2-N, N-di amino) ethyl] phenyl } Pyruvic Acid Methyl ester sylvite
According to embodiment () similar techniques scheme, oxalic acid diethyl ester is replaced by dimethyl oxalate, can obtain the red solid product of { 2-nitro-6-[(2-N, N-di amino) ethyl] phenyl } Pyruvic Acid Methyl ester sylvite, yield 49.9%.
Embodiment (four)
2-nitro-6-[(2-N, N-di amino) and ethyl] phenyl } the Pyruvic Acid Methyl ester sodium salt
According to embodiment (two) similar techniques scheme, oxalic acid diethyl ester is replaced by dimethyl oxalate, can obtain the red solid product of { 2-nitro-6-[(2-N, N-di amino) ethyl] phenyl } Pyruvic Acid Methyl ester sodium salt, yield 43.2%.
Claims (8)
1. the stable form (V) of general formula (X) compound
Wherein R is methyl or ethyl, and M is sodium Metal 99.5 or potassium metal.
2. the stable form (V) of the general formula of claim 1 (X) compound is characterized in that R=CH
3, M=K.
3. the stable form (V) of the general formula of claim 1 (X) compound is characterized in that R=CH
3, M=Na.
4. the stable form (V) of the general formula of claim 1 (X) compound is characterized in that R=C
2H
5, M=K.
5. the stable form (V) of the general formula of claim 1 (X) compound is characterized in that R=C
2H
5, M=Na.
6. the preparation process of the stable form (V) of the general formula of claim 1 (X) compound may further comprise the steps:
(1) metal M is suspended in the anhydrous aprotic solvent, adds anhydrous alcohol reagent to prepare the alkoxide of fresh metal M;
～-10 ℃ (2)-20 in above-mentioned reaction solution, be added dropwise to N, N-di-2-methyl-3-nitro phenylethylamine, insulated and stirred 1-2 hour under;
～-10 ℃ (3)-20 drip dimethyl oxalate or oxalic acid diethyl ester, insulated and stirred 12-24 hour down;
(4) filter, obtain the red solid precipitation, dry 5-15 hour, promptly get logical formula V compound.
7. according to the preparation method of claim 6 description, used aprotic solvent is tetrahydrofuran (THF) or ether;
8. according to the preparation method of claim 6 description, used alcohol reagent is methyl alcohol or ethanol.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115340460A (en) * | 2022-09-21 | 2022-11-15 | 江西亚太科技发展有限公司 | Method for synthesizing Reissert indole synthesis reaction intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4452808A (en) * | 1982-12-07 | 1984-06-05 | Smithkline Beckman Corporation | 4-Aminoalkyl-2(3H)-indolones |
| CN1754874A (en) * | 2004-09-28 | 2006-04-05 | 北京德众万全医药科技有限公司 | Process for preparing ropinirole and its salt |
| WO2006123356A1 (en) * | 2005-02-15 | 2006-11-23 | Alembic Limited | Process for the preparation of indolone derivative |
| WO2008084499A1 (en) * | 2007-01-10 | 2008-07-17 | Ind-Swift Laboratories Limited | An industrial process for the preparation of pure ropinirole |
| CN101585773A (en) * | 2009-05-22 | 2009-11-25 | 江苏开元医药化工有限公司 | Method for preparing N-(2-methyl-3-nitro)-N-propyl-1-propylamin hydrochloride |
-
2010
- 2010-07-27 CN CN201010237662.2A patent/CN101891641B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4452808A (en) * | 1982-12-07 | 1984-06-05 | Smithkline Beckman Corporation | 4-Aminoalkyl-2(3H)-indolones |
| CN1754874A (en) * | 2004-09-28 | 2006-04-05 | 北京德众万全医药科技有限公司 | Process for preparing ropinirole and its salt |
| WO2006123356A1 (en) * | 2005-02-15 | 2006-11-23 | Alembic Limited | Process for the preparation of indolone derivative |
| WO2008084499A1 (en) * | 2007-01-10 | 2008-07-17 | Ind-Swift Laboratories Limited | An industrial process for the preparation of pure ropinirole |
| CN101585773A (en) * | 2009-05-22 | 2009-11-25 | 江苏开元医药化工有限公司 | Method for preparing N-(2-methyl-3-nitro)-N-propyl-1-propylamin hydrochloride |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115340460A (en) * | 2022-09-21 | 2022-11-15 | 江西亚太科技发展有限公司 | Method for synthesizing Reissert indole synthesis reaction intermediate |
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