CN106565520A - Safinamide mesylate preparation method - Google Patents
Safinamide mesylate preparation method Download PDFInfo
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- CN106565520A CN106565520A CN201510644432.0A CN201510644432A CN106565520A CN 106565520 A CN106565520 A CN 106565520A CN 201510644432 A CN201510644432 A CN 201510644432A CN 106565520 A CN106565520 A CN 106565520A
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- benzaldehyde
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Abstract
The present invention belongs to the field of pharmaceutical synthesis, and provides a new safinamide mesylate preparation method. According to the present invention, m-fluorobenzyl chloride and p-hydroxybenzaldehyde are adopted as starting raw materials, and etherification, aldehyde amine condensation, reduction, salt forming and refinement are performed to obtain the final product; and the method has advantages of simple process and high yield, and is suitable for industrial production, wherein the product purity achieves more than 99.95%.
Description
Technical field：
The invention belongs to pharmaceutical synthesis field, more particularly to a kind of synthetic method of anti-Parkinson medicine methanesulfonic acid FCE-26743A.
Background technology：
Methanesulfonic acid FCE-26743A is the alpha-aminoamide derivatives developed by Newron companies, is worked by various unique mechanism of action.Methanesulfonic acid FCE-26743A belongs to sodium and calcium channel complex blocking agent, is again monoamine oxidase-B（MAO-B）Inhibitor, it passes through blocking voltage dependent form sodium, calcium channel and suppresses glutamic neuron, selectivity, reversibly suppresses monoamine oxidase-B, can also suppress the degeneration of cyton.Clinical trial shows, FCE-26743A is combined with DA agonist, can substantially mitigate tremble, the motor symptoms such as dyskinesia.
The at present synthesis with regard to methanesulfonic acid FCE-26743A of document report is simultaneously few, and relevant document report mainly has a JMC, and 2007,50 (20), 4909-4916 and Synthesis, 2014,46,1751-1756 and JMC, 1998,41 (4), 579-590.
Principal synthetic routes are as follows：
Method one：Document report uses solid-phase synthesis, Rink amide resin hydrolyzing decarboxylizes, with（S）-2-（Fluorenes methoxy amide groups）Propanoic acid occur ammonolysis reaction, slough after amino protecting group with 4-（Tri isopropyl siloxany）Benzaldehyde, Jing sodium triacetoxy borohydrides reduction, then sloughs after phenolic hydroxyl protecting group again with 3- fluoro benzyl alcohols into ether, finally takes off product under resin, obtains final product FCE-26743A.
Method two：
Method three：
Method one is solid phase synthesis, it is difficult to industrialized production；The synthetic route of method two is long, and the more difficult control of intermediate, yield is low；Synthetic route described in method three is relatively reasonable due to its Process Route Planning, and reaction condition is gentle, and yield preferably, is relatively more suitable for industrial-scale production, so, it is in actual production at present to adopt method three more.
Our company finds that there are the following problems in prior art during studying above-mentioned process route：1. between in fluorobenzyl chloride and hydroxy benzaldehyde etherification reaction step, extraction mode is taken in post processing, and intermediate obtained by concentrating carries out recrystallization using toluene equal solvent, is unfavorable for industrialized production；2. aldimine condensation and reduction reaction are even thrown in step, and reducing agent used is Pd/C hydrogen, and operational hazards are unfavorable for industrialized production；3. when methanesulfonic acid FCE-26743A is prepared, (S) -2- [4- (3- fluorine benzyloxies) benzene methanamine base] propionic acid amide. is refining to obtain using two class toxic solvents, then directly into salt.
For the problems referred to above of prior art, the present invention propose a kind of simple reactions steps, post processing simple purification, be more suitable for industrialized production methanesulfonic acid FCE-26743A preparation method.
The content of the invention
Present invention aims to problem present on existing methanesulfonic acid FCE-26743A synthetic method, it is proposed that a kind of reactions steps are simple, post processing simple purification, purity are high, be more suitable for industrialized production methanesulfonic acid FCE-26743A preparation method.
To achieve these goals, the present invention is adopted the following technical scheme that：
1st, a kind of synthetic method of methanesulfonic acid FCE-26743A, it is characterised in that comprise the steps：
（1）With a fluorobenzyl chloride and hydroxy benzaldehyde as initiation material, selection potassium carbonate is acid binding agent, and potassium iodide is catalyst, and ethanol serves as reaction dissolvent and etherification reaction occurs, and obtains 4-（3- fluorine benzyloxies）Benzaldehyde：
（2）4-（3- fluorine benzyloxies）There is aldimine condensation reaction and then and KBH with L- aminopropanamide hydrochlorate in benzaldehyde4Generation reduction reaction, obtains (S) -2- [4- (3- fluorine benzyloxies) benzene methanamine base] propionic acid amide.：
（3）(S) -2- [4- (3- fluorine benzyloxies) benzene methanamine base] propionic acid amide .s obtain methanesulfonic acid FCE-26743A crude product with methanesulfonic acid into salt：
（4）Methanesulfonic acid FCE-26743A crude product carries out recrystallization with ethanol as solvent, obtains methanesulfonic acid FCE-26743A finished product.
2nd, a kind of synthetic method as claimed in claim 1, it is characterised in that step（1）In, the post processing solvent is water, and a fluorobenzyl chloride is 1 with water quality volume ratio：5；Post-processing temperature is 0-30 DEG C, preferably 20-25 DEG C.
3rd, a kind of synthetic method as claimed in claim 1, it is characterised in that step（2）In aldimine condensation reaction and reduction reaction be that two steps even throw reaction, reducing agent selects have KBH4、NaBH4, Pd/C hydrogen, NaBH3CN, preferred KBH4Work as reducing agent；4-（3- fluorine benzyloxies）Benzaldehyde and KBH4Mol ratio is 1：4~1：8, preferably 1：6；
4th, a kind of synthetic method as claimed in claim 1, it is characterised in that step（4）Middle recrystallization solvent is preferably ethanol.
Compared with prior art, the present invention has the advantages that：1. the present invention is preparing intermediate 4-（3- fluorine benzyloxies）In the step of benzaldehyde, post processing takes water for solvent, room temperature is cooled to after completion of the reaction and is added water stirring, sucking filtration, simple to operate, more conducively industrialized production, while avoiding having used two class solvent toluenes；2. aldimine condensation and reduction reaction are even thrown in step and take KBH4 Reducing agent is made, reaction condition is gentle, safer compared with Pd/C hydrogen, more conducively industrialized production, and avoid the introducing of heavy metal Pd, be conducive to the carrying out of subsequent step；3. methanesulfonic acid FCE-26743A crude product carries out recrystallization with ethanol as solvent, it is to avoid using two class solvents such as toluene, obtains the finished product of purity more than 99.95%, and can preferably remove the residual solvent for walking into salt.
The simple synthetic method of methanesulfonic acid FCE-26743A of the present invention is easily-controllable, post-processing operation is simple, purity is high, be more beneficial for industrialized production, and there is supply in institute using the raw material country, and environmental pollution is little, and raw material is cheap and easy to get.Therefore the new method for preparing methanesulfonic acid FCE-26743A that the present invention is provided has wide commercial application prospect.
Specific embodiment
In order to be better understood from the present invention, with reference to embodiment to further detailed description of the invention.
Embodiment
1
By 88.70g（0.73mol）Hydroxy benzaldehyde is added in 1000ml reaction bulbs, plus ethanol 500ml, plus K2CO3
105.10g（0.76mol）, 30min is stirred at room temperature, fluorobenzyl chloride 100.00g between then adding（0.69mol）, KI 9.20g（0.06mol）, it is refluxed reaction 4h.After completion of the reaction, room temperature is cooled to, plus 500ml water stirs 1h, sucking filtration, filter cake adds 1000ml water to stir 1h, and sucking filtration, drying at room temperature filter cake 24h obtains white solid 4-（3- fluorine benzyloxies）Benzaldehyde 137.10g, yield：86.2%.HPLC purity is：99.82%.
Embodiment
2
By L- aminopropanamide hydrochlorate 84.41g（0.68mol）In being added to reaction bulb, plus triethylamine 171.42g（1.69mol）Then plus 4-, methanol 1300ml is stirred at room temperature 30min,（3- fluorine benzyloxies）Benzaldehyde 130.11g（0.56mol）, 2h is stirred at room temperature.Plus KBH then4182.71g（3.39mol）, it is refluxed overnight.After completion of the reaction, reactant liquor is concentrated to dryness, plus 1300ml water is stirred at room temperature 1h, sucking filtration, 40 DEG C of vacuum drying 4h obtain white solid (S) -2- [4- (3- fluorine benzyloxies) benzene methanamine base] propionic acid amide. 163.92g, yield：96.0%.HPLC purity is：99.04%.
Embodiment
3
By (S) -2- [4- (3- fluorine benzyloxies) benzene methanamine base] propionic acid amide. 160.00g（0.53mol）In being added to reaction bulb, plus ethyl acetate 3200ml, backflow is warming up to, stirring is complete molten, is refluxed 1h, lowers the temperature, and methanesulfonic acid 38ml is added at a temperature of 50 DEG C -55 DEG C（0.58mol）, stirring after adding and be cooled to room temperature, sucking filtration, 40 DEG C of vacuum drying 3h obtain white solid methanesulfonic acid FCE-26743A crude product 189.8g, yield：90.0%.HPLC purity is：99.80%.
Embodiment
4
By methanesulfonic acid FCE-26743A crude product 180.02g（0.45mol）In being added to reaction bulb, plus ethanol 1260ml, backflow is warming up to, stirring is complete molten, is refluxed 1h, is cooled to room temperature, and sucking filtration, 40 DEG C of vacuum drying 3h obtain white solid methanesulfonic acid FCE-26743A finished product 149.60g, yield：83.1%.HPLC purity is：99.98%.
Claims (4)
1. a kind of synthetic method of methanesulfonic acid FCE-26743A, it is characterised in that comprise the steps：
（1）With a fluorobenzyl chloride and hydroxy benzaldehyde as initiation material, selection potassium carbonate is acid binding agent, and potassium iodide is catalyst, and ethanol serves as reaction dissolvent and etherification reaction occurs, and obtains 4-（3- fluorine benzyloxies）Benzaldehyde：
（2）4-（3- fluorine benzyloxies）There is aldimine condensation reaction and then and KBH with L- aminopropanamide hydrochlorate in benzaldehyde4Generation reduction reaction, obtains (S) -2- [4- (3- fluorine benzyloxies) benzene methanamine base] propionic acid amide.：
（3）(S) -2- [4- (3- fluorine benzyloxies) benzene methanamine base] propionic acid amide .s obtain methanesulfonic acid FCE-26743A crude product with methanesulfonic acid into salt：
（4）Methanesulfonic acid FCE-26743A crude product carries out recrystallization with ethanol as solvent.
2. a kind of synthetic method as claimed in claim 1, it is characterised in that step（1）In, the post processing solvent is water, and a fluorobenzyl chloride is 1 with water molal volume ratio：5；Post-processing temperature is 0-30 DEG C, preferably 20-25 DEG C.
3. a kind of synthetic method as claimed in claim 1, it is characterised in that step（2）In aldimine condensation reaction and reduction reaction be that two steps even throw reaction, reducing agent selects have KBH4、NaBH4, Pd/C hydrogen, NaBH3CN, preferred KBH4Work as reducing agent；4-（3- fluorine benzyloxies）Benzaldehyde and KBH4Mol ratio is 1：4~1：8, preferably 1：6.
4. a kind of synthetic method as claimed in claim 1, it is characterised in that step（4）Middle recrystallization solvent is preferably ethanol.
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| CN201510644432.0A CN106565520A (en) | 2015-10-09 | 2015-10-09 | Safinamide mesylate preparation method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106977382A (en) * | 2017-04-28 | 2017-07-25 | 山东新华制药股份有限公司 | 4‑（3 fluorine benzyloxies）The preparation method of benzaldehyde |
| CN111689871A (en) * | 2019-03-14 | 2020-09-22 | 北京万全德众医药生物技术有限公司 | Synthetic preparation of safinamide mesylate |
| US11225457B2 (en) | 2019-08-06 | 2022-01-18 | Medichem, S.A. | Process for preparing safinamide |
-
2015
- 2015-10-09 CN CN201510644432.0A patent/CN106565520A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106977382A (en) * | 2017-04-28 | 2017-07-25 | 山东新华制药股份有限公司 | 4‑（3 fluorine benzyloxies）The preparation method of benzaldehyde |
| CN111689871A (en) * | 2019-03-14 | 2020-09-22 | 北京万全德众医药生物技术有限公司 | Synthetic preparation of safinamide mesylate |
| US11225457B2 (en) | 2019-08-06 | 2022-01-18 | Medichem, S.A. | Process for preparing safinamide |
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Application publication date: 20170419 |