CN102260209A - Preparation method of flupirtine maleate - Google Patents
Preparation method of flupirtine maleate Download PDFInfo
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- CN102260209A CN102260209A CN2011101412452A CN201110141245A CN102260209A CN 102260209 A CN102260209 A CN 102260209A CN 2011101412452 A CN2011101412452 A CN 2011101412452A CN 201110141245 A CN201110141245 A CN 201110141245A CN 102260209 A CN102260209 A CN 102260209A
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Abstract
The invention discloses a preparation method of flupirtine maleate. The method comprises the following steps: mixing a reactant A with a catalyst and a solvent and then carrying out hydrogen transfer reduction reaction so as to obtain a first product B; dropwise adding an alkali reagent and ethyl chloroformate to the first product B for reaction so as to obtain a second product C; and adding a maleic acid solution to the second product C for reaction so as to obtain the flupirtine maleate product D. The invention aims to provide a method for preparing flupirtine maleate, which is different from known methods. By using the method, the reaction can be completed at normal pressure; and reaction conditions are simple, cost is low, and the prepared product has high purity.
Description
Technical field
The present invention is specifically related to a kind of preparation method of toxilic acid flupirtine.
Background technology
The chemical name of toxilic acid flupirtine is 2-amino-6-(((4-fluorophenyl) methyl) amino)-3-pyridyl) the urethanum maleate, its structural formula is as follows:
The toxilic acid flupirtine is a kind of novel non-opium central analgesics of German AWD company development, oral easy absorption, and the pain that multiple reason is caused all has analgesic activity, has pain relieving, of flaccid muscles and neuroprotective three efficacy.Do not have avidity with opiate receptor, also do not suppress the synthetic of prostaglandin(PG), not by the naloxone antagonism, analgesia is tired and is equated that with pentazocine be about 50% of morphine, apnea and cardiovascular systems restraining effect do not produce constipation and uroschesis yet.Take for a long time and do not produce tolerance and dependency.
Document reports its synthetic method, but the mode of the high-pressure hydrogenation that all reports all are to use the reduction of nitro finish, the present invention has avoided the mode of high-pressure hydrogenation fully, finishes reaction under normal pressure.
Summary of the invention
For solving the problems of the technologies described above, the present invention proposes a kind of preparation method of new toxilic acid flupirtine, this method can be finished under normal pressure, and reaction conditions is simple, and cost is low and product purity is high.
For achieving the above object, technical scheme of the present invention is as follows:
A kind of preparation method of toxilic acid flupirtine, it comprises:
Step I, reactant A and catalyzer and solvent carried out the hydrogen transfer reduction reaction obtain the first resultant B:
Step II, drip alkali reagent and Vinyl chloroformate in the described first resultant B, reaction obtains the second resultant C:
Step II I, add maleic acid solution in the described second resultant C, reaction obtains toxilic acid flupirtine product D:
Preferably, the described catalyzer among the described step I is Pd/C and ammonium formiate, or Raney's nickel and ammonium formiate, or reduced iron powder and hydrochloric acid.
Preferably, described solvent is C
1-C
5Pure and mild tetrahydrofuran (THF).
Preferably, described solvent is an ethanol.
Preferably, required temperature of reaction is 60 ℃-90 ℃ among the described step I; Reaction times is 2-5h.
Pass through technique scheme, a kind of method for preparing the toxilic acid flupirtine disclosed in this invention, be that reduction to nitro is to adopt the mode of catalytic transfer hydrogenation reaction to carry out, avoided the reactive mode of high temperature hydrogenation, reaction conditions is simple, and reaction raw materials obtains easily, and cost is low, and the product yield height.
Embodiment
The invention will be further elaborated by following examples.
Embodiment one
Reactant A is got 150g, ethanol 1.5L, and 10% Pd/C7.5g and 72g ammonium formiate are put into the 3L there-necked flask, carry out reduction reaction under 70 ℃ temperature environment, and the reaction times is 5h, can obtain the first resultant B, and be cooled to room temperature; Under nitrogen protection, drip Vinyl chloroformate 72g, drip triethylamine 75g, add back stirring 1.5h and react, obtain the second resultant C; With reacting liquid filtering, filtrate is transferred in the 5L there-necked flask, has prepared 108g toxilic acid and 1.5L water in the there-necked flask in advance, stirs 4h under 20 ℃-25 ℃ temperature environment, filters to obtain toxilic acid flupirtine product; With resulting toxilic acid flupirtine product alcohol crystal, obtain the pure product 142g of toxilic acid flupirtine, yield is 59.3%.
Embodiment two
Reactant A is got 150g, ethanol 1.5L, and Raney's nickel 15g and 72g ammonium formiate are put into the 3L there-necked flask, carry out reduction reaction under 70 ℃ temperature environment, and the reaction times is 5h, can obtain the first resultant B, and be cooled to room temperature; Under nitrogen protection, drip Vinyl chloroformate 72g, drip triethylamine 75g, add back stirring 1.5h and react, obtain the second resultant C; With reacting liquid filtering, filtrate is transferred in the 5L there-necked flask, has prepared 108g toxilic acid and 1.5L water in the there-necked flask in advance, stirs 4h under 20 ℃-25 ℃ temperature environment, filters to obtain toxilic acid flupirtine product; With resulting toxilic acid flupirtine product alcohol crystal, obtain the pure product 140g of toxilic acid flupirtine, yield is 58.5%.
Embodiment three
Reactant A is got 150g, ethanol 1.5L, and Raney's nickel 15g and hydrazine hydrate 28.6g put into the 3L there-necked flask, carry out reduction reaction under 70 ℃ temperature environment, and the reaction times is 2h, can obtain the first resultant B, and be cooled to room temperature; Under nitrogen protection, drip Vinyl chloroformate 72g, drip triethylamine 75g, add back stirring 1.5h and react, obtain the second resultant C; With reacting liquid filtering, filtrate is transferred in the 5L there-necked flask, has prepared 108g toxilic acid and 1.5L water in the there-necked flask in advance, stirs 4h under 20 ℃-25 ℃ temperature environment, filters to obtain toxilic acid flupirtine product; With resulting toxilic acid flupirtine product alcohol crystal, obtain the pure product 140g of toxilic acid flupirtine, yield is 58.5%.
The invention discloses a kind of method for preparing the toxilic acid flupirtine, the reduction to nitro in this method is to adopt the mode of catalytic transfer hydrogenation reaction to carry out, and has avoided the reactive mode of high temperature hydrogenation, reaction conditions is simple, and reaction raw materials obtains easily, and cost is low, and the product yield height.
The explanation of above embodiment just helps to help to understand method of the present invention and core concept thereof.For those of ordinary skill in the art, under the prerequisite that does not break away from the principle of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also should fall in the protection domain of claim of the present invention.
Claims (5)
1. the preparation method of a toxilic acid flupirtine is characterized in that, comprising:
Step I, reactant A and catalyzer and solvent carried out the hydrogen transfer reduction reaction obtain the first resultant B:
Step II, drip alkali reagent and Vinyl chloroformate in the described first resultant B, reaction obtains the second resultant C:
Step II I, add maleic acid solution in the described second resultant C, reaction obtains toxilic acid flupirtine product D:
2. preparation method according to claim 1 is characterized in that, the described catalyzer among the described step I is Pd/C and ammonium formiate, or Raney's nickel and ammonium formiate, or reduced iron powder and hydrochloric acid.
3. preparation method according to claim 1 is characterized in that, described solvent is C
1-C
5Pure and mild tetrahydrofuran (THF).
4. preparation method according to claim 3 is characterized in that described solvent is preferably ethanol.
5. according to each described preparation method of claim 1-4, it is characterized in that required temperature of reaction is 60 ℃-90 ℃ among the described step I; Reaction times is 2-5h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101412452A CN102260209A (en) | 2011-05-27 | 2011-05-27 | Preparation method of flupirtine maleate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101412452A CN102260209A (en) | 2011-05-27 | 2011-05-27 | Preparation method of flupirtine maleate |
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| Publication Number | Publication Date |
|---|---|
| CN102260209A true CN102260209A (en) | 2011-11-30 |
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|---|---|---|---|
| CN2011101412452A Pending CN102260209A (en) | 2011-05-27 | 2011-05-27 | Preparation method of flupirtine maleate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541705A (en) * | 2015-12-31 | 2016-05-04 | 山东罗欣药业集团股份有限公司 | Synthesis method for flupirtine maleate compound |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010136113A1 (en) * | 2009-05-29 | 2010-12-02 | Corden Pharmachem Gmbh | Method for producing flupirtine |
-
2011
- 2011-05-27 CN CN2011101412452A patent/CN102260209A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010136113A1 (en) * | 2009-05-29 | 2010-12-02 | Corden Pharmachem Gmbh | Method for producing flupirtine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541705A (en) * | 2015-12-31 | 2016-05-04 | 山东罗欣药业集团股份有限公司 | Synthesis method for flupirtine maleate compound |
| CN105541705B (en) * | 2015-12-31 | 2019-08-06 | 山东罗欣药业集团恒欣药业有限公司 | A kind of synthetic method of flupirtine maleate compound |
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Application publication date: 20111130 |