CN103113256A - Synthetizing method of lacosamide - Google Patents
Synthetizing method of lacosamide Download PDFInfo
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- CN103113256A CN103113256A CN 201110365255 CN201110365255A CN103113256A CN 103113256 A CN103113256 A CN 103113256A CN 201110365255 CN201110365255 CN 201110365255 CN 201110365255 A CN201110365255 A CN 201110365255A CN 103113256 A CN103113256 A CN 103113256A
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Abstract
The invention provides a synthetizing method of lacosamide. The method comprises the steps of: based on D-serine as a raw material, performing an acylation reaction with acetic anhydride and then performing a condensation reaction with benzylamine; and finally, performing a methylation reaction with dimethyl sulfate, thereby obtaining lacosamide, wherein N,N' dicyclohexylcarbodiimide (DCC) or N,N' carbonyl diimidazole (CDI) is used as a catalyst in the condensation reaction; and a phase transfer catalyst including triethyl benzyl ammonium chloride (TEBA), tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB) or tetrabutylammonium hydrogen sulfate (TBAHS) is adopted in the methylation reaction. The method has the advantages of being simple in synthetizing process, moderate in reaction condition, simple in after-treatment, high in yield and high in product purity.
Description
Technical field
The present invention relates to a kind of synthetic method of scheme for lacosamide, belong to technical field of pharmaceutical chemistry.
Background technology
Scheme for lacosamide (Lacosamide), chemical name are (R)-2-acetamido-N-benzyl-3-methoxy propionamide, are the treatment epilepsy of German Schwarz Pharma company research and development and the medicine of neuropathic pain.The scheme for lacosamide sheet listing of the Belgian UCB. S.A. (BE) Bruxelles Belgium of in September, 2008 European Union approval, be used for assisting therapy 16 years old and more than have or without secondary epilepsy grand mal patient's epilepsy partial seizure.In October, 2008, the listing of drugs approved by FDA scheme for lacosamide, united for the epilepsy partial seizures as a kind of ancillary drug and other drug, and commodity are called Vimpat.Scheme for lacosamide is the anticonvulsant drug with brand-new double mechanism effect, promote the slow inactivation in sodium channel and regulate the reaction mediating proteins 22 (CRMP22) that subsides by selectivity, thereby reach the effect of slowing down and even stoping epileptic seizures and alleviating the neuropathic pain of diabetes.
Synthesizing all take D-Ser as raw material of scheme for lacosamide; existing technique is generally first by protecting amino with reactions such as triphenylmethyl chloride, chloroformic acid benzyl ester, isobutyl chlorocarbonates; again with the benzylamine condensation; then with methyl iodide or methyl-sulfate generation methylation reaction; acetylize again, last deprotection obtains scheme for lacosamide.Condensation and methylated reaction have first have after, but amino protection process is indispensable step.Such synthetic schemes step is long, and cost is high, and complex operation and total recovery are low.
Summary of the invention
The objective of the invention is to overcome the deficiency that prior art exists, a kind of synthetic method of new scheme for lacosamide is provided, be intended to reduce reactions steps, reduce costs, improve the yield of reaction.
Purpose of the present invention is achieved through the following technical solutions:
A kind of synthetic method of scheme for lacosamide, take D-Ser (I) as raw material, first with acetic anhydride generation acylation reaction, then with benzylamine generation condensation reaction, last and methyl-sulfate generation methylation reaction obtains product.Comprise the steps:
(1) first I is dissolved in solvent, acylation reaction occurs in cooling lower dropping acetic anhydride, and reaction adds entry after finishing, isolate organic phase, after washing, merge organic phase and be concentrated into driedly, add ether to disperse, filter, drying gets (R)-2-acetylaminohydroxyphenylarsonic acid 3-hydroxy-propionic acid (II);
(2) II is dissolved in solvent, adds catalyzer, add benzylamine after reaction, condensation reaction occurs.Reaction finishes to obtain (R)-2-acetylaminohydroxyphenylarsonic acid 3-hydroxy-n-benzyl propionic acid amide (III) by processing later;
(3) III is dissolved in solvent, adds catalyzer, add NaOH solution and methyl-sulfate after cooling, methylation reaction occurs.Washing after reaction finishes merges organic phase, be concentrated into dried, and with obtaining scheme for lacosamide after re-crystallizing in ethyl acetate.
Further, the synthetic method of above-mentioned a kind of scheme for lacosamide is characterized in that: the reaction solvent described in above three-step reaction is: methylene dichloride, chloroform, toluene, tetrahydrofuran (THF), DMF.
Further, the synthetic method of above-mentioned a kind of scheme for lacosamide, it is characterized in that: the temperature that drips acetic anhydride described in step (1) is: 0～20 ℃, reaction conditions is: reacted under 25～35 ℃ 1～5 hour, the mol ratio of D-Ser and acetic anhydride is 1:(1～2).
Further, the synthetic method of above-mentioned a kind of scheme for lacosamide is characterized in that: described in step (2), catalyzer is: N, N '-dicyclohexylcarbodiimide (DCC), N, N '-carbonyl dimidazoles (CDI), the mol ratio of II and catalyzer are 1:(1～1.2).
Again further, the synthetic method of above-mentioned a kind of scheme for lacosamide is characterized in that: add the reaction conditions after catalyzer to be in step (2): reacted under 25～35 ℃ 0.5～2 hour, the condensation reaction condition is for to react under 25～35 ℃ 1～5 hour.
Again further, the synthetic method of above-mentioned a kind of scheme for lacosamide, it is characterized in that: catalyzer is in step (3): a kind of in benzyltriethylammoinium chloride (TEBA), tetrabutylammonium chloride (TBAC), Tetrabutyl amonium bromide (TBAB), 4-butyl ammonium hydrogen sulfate (TBAHS), the mass ratio of III and catalyzer is: (20～60): 1, and the mol ratio of III and methyl-sulfate is: 1:(1～6).
Again further, the synthetic method of above-mentioned a kind of scheme for lacosamide is characterized in that: in step (3), temperature of reaction system is :-2～10 ℃, the methylation reaction time is 1～8 hour.
The substantive distinguishing features that technical solution of the present invention is outstanding and significant progressive being mainly reflected in:
The present invention utilizes D-Ser to be raw material; first with acetic anhydride generation acetylization reaction; under the catalysis of DCC, CDI, condensation reaction occurs with benzylamine again, methylation reaction occurs and obtains product in last and methyl-sulfate under the catalysis of TEBA, TBAC, TBAHS, TBAB.Reactions steps is short, amino is not protected with other group, has reduced the reactions steps of protection and deprotection, and reaction conditions is gentle, does not need high temperature and high pressure environment.In addition, adopt efficient catalyzer to carry out condensation and methylation reaction, improved the transformation efficiency of reaction.
Description of drawings
Below in conjunction with accompanying drawing, technical solution of the present invention is described further:
Fig. 1: acetylization reaction schematic diagram;
Fig. 2: condensation reaction schematic diagram;
Fig. 3: methylation reaction schematic diagram.
Embodiment
Embodiment 1
Acylation reaction
Add the 150ml methylene dichloride in reaction flask, add the 10.5gD-Serine under stirring, be cooled to 10～15 ℃ and drip the 11.3ml acetic anhydride, keep this temperature and drip approximately 20 minutes, be warming up to 25～30 ℃ of reactions 1 hour.Reaction adds 50ml water after finishing, and isolates organic phase, uses 8%Na
2CO
3The 50ml washing, then use 50ml water washing twice, merge organic phase, steaming desolventizes, then adds the 100ml ether to disperse to stir, and separates out white solid, filters, and dries to get 14.2g(R)-2-acetylaminohydroxyphenylarsonic acid 3-hydroxy-propionic acid (II).
Embodiment 2
Acylation reaction
Add the 150ml chloroform in reaction flask, add the 10.5gD-Serine under stirring, be cooled to 10～15 ℃ and drip the 14.2ml acetic anhydride, keep this temperature and drip approximately 30 minutes, be warming up to 25～30 ℃ of reactions 1.5 hours.Reaction adds 50ml water after finishing, and isolates organic phase, uses 8%Na
2CO
3The 30ml washed twice, then use 50ml water washing twice, merging organic phase, steaming desolventizes, then adds the 100ml ether to disperse to stir, and separates out white solid, filters, and dries to get the 13.9g II.
Embodiment 3
Condensation reaction
Add the 150ml methylene dichloride in reaction flask, add II 10.3g under stirring, after dissolving, the 15.6gDCC that dropping prepares is dissolved in the solution of 60ml methylene dichloride, after 0.5 hour, adds benzylamine 7.5g in 25～30 ℃ of reactions, in 25～30 ℃ of reactions 3 hours, whether some plate judgement reaction was complete.Filter after reaction finishes, filtrate merges organic layer with 50ml water washing 3 times, be concentrated into do after, add 20ml chloroform-80ml methyl tertiary butyl ether mixed solvent recrystallization, obtain (R)-2-acetylaminohydroxyphenylarsonic acid 3-hydroxy-n-benzyl propionic acid amide (III) 12.4 g.
Embodiment 4
Condensation reaction
Add 120mlTHF in reaction flask, add II 10.3g under stirring, after dissolving, add HOBt4.7g, add the 11.35gCDI that configures to be dissolved in the THF solution of 60ml under cooling, after 1 hour, add benzylamine 7.5g in 25～30 ℃ of reactions, in 25～30 ℃ of reactions 3 hours, whether some plate judgement reaction was complete.Filter after reaction finishes, filtrate merges organic phase with 50ml water washing 3 times, be concentrated into do after, add entry 100ml, with 30ml chloroform extraction 3 times, merge organic phase, after drying, be concentrated into driedly, add the 100ml ether to disperse to obtain III 13.2g.
Embodiment 5
Methylation reaction
Add the 150ml methylene dichloride in reaction flask, add III 11.8g and catalyzer Tetrabutyl amonium bromide (TBAB) 0.4g under stirring, be cooled to 0～5 ℃, add 10ml 20%NaOH, stirred 1 hour, and kept this temperature and add 15ml methyl-sulfate, 18ml 50%NaOH, stirred 2 hours.Reaction is washed to neutrality with dilute hydrochloric acid after finishing, with 50ml washing 3 times.Organic phase merges, and is concentrated into driedly, and the 50ml re-crystallizing in ethyl acetate obtains the 11.5g scheme for lacosamide, purity 99.2%.
Embodiment 6
Methylation reaction
Add 150ml toluene in reaction flask, add III 11.8g and catalyzer benzyltriethylammoinium chloride (TEBA) 0.3g under stirring, be cooled to 0～5 ℃, add 30ml 20%NaOH, stirred 0.5 hour, and kept this temperature and add the 19ml methyl-sulfate, stirred 4 hours.Reaction is washed to neutrality with dilute hydrochloric acid after finishing, with 50ml washing 3 times.Organic phase merges, and is concentrated into driedly, obtains the 11.8g scheme for lacosamide with the 50ml re-crystallizing in ethyl acetate, purity 99.8%.
Reaction conditions of the present invention is gentle, and yield is high, and condensation reaction and methylation reaction have used effective catalyst, reaction yield is improved, and the purity of product is good, and the total recovery of reaction can reach: 73%, and product purity can reach: 99.8%.
What need to understand is: the above is only the preferred embodiment of the present invention; for those skilled in the art; under the prerequisite that does not break away from the principle of the invention, can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (7)
1. the synthetic method of a scheme for lacosamide, take D-Ser (I) as raw material, first with acetic anhydride generation acylation reaction, then with benzylamine generation condensation reaction, last and methyl-sulfate generation methylation reaction obtains product, comprises the steps:
(1) first I is dissolved in solvent, acylation reaction occurs in cooling lower dropping acetic anhydride, and reaction adds entry after finishing, isolate organic phase, after washing, merge organic phase and be concentrated into driedly, add ether to disperse, filter, drying gets (R)-2-acetylaminohydroxyphenylarsonic acid 3-hydroxy-propionic acid (II);
(2) II is dissolved in solvent, adds catalyzer, add benzylamine after reaction, condensation reaction occurs, reaction finishes to obtain (R)-2-acetylaminohydroxyphenylarsonic acid 3-hydroxy-n-benzyl propionic acid amide (III) by processing later;
(3) III is dissolved in solvent, adds catalyzer, add NaOH solution and methyl-sulfate under cooling conditions, methylation reaction occurs, washing after reaction finishes merges organic phase, be concentrated into dried, with obtaining scheme for lacosamide after re-crystallizing in ethyl acetate.
2. the synthetic method of a kind of scheme for lacosamide according to claim 1, it is characterized in that: the reaction solvent described in above three-step reaction is: methylene dichloride, chloroform, toluene, tetrahydrofuran (THF), DMF.
3. the synthetic method of a kind of scheme for lacosamide according to claim 1, it is characterized in that: the temperature that drips acetic anhydride described in step (1) is: 0～20 ℃, reaction conditions is: reacted under 25～35 ℃ 1～5 hour, the mol ratio of D-Ser and acetic anhydride is 1:(1～2).
4. the synthetic method of a kind of scheme for lacosamide according to claim 1, it is characterized in that: described in step (2), catalyzer is: N, N '-dicyclohexylcarbodiimide (DCC), N, N '-carbonyl dimidazoles (CDI), the mol ratio of II and catalyzer is 1:(1～1.2).
5. the synthetic method of a kind of scheme for lacosamide according to claim 1, it is characterized in that: add the reaction conditions after catalyzer to be in step (2): reacted under 25～35 ℃ 0.5～2 hour, the condensation reaction condition is for to react 1～5 hour under 25～35 ℃.
6. the synthetic method of a kind of scheme for lacosamide according to claim 1, it is characterized in that: catalyzer is in step (3): a kind of in benzyltriethylammoinium chloride (TEBA), tetrabutylammonium chloride (TBAC), Tetrabutyl amonium bromide (TBAB), 4-butyl ammonium hydrogen sulfate (TBAHS), the mass ratio of III and catalyzer is: (20～60): 1, and the mol ratio of III and methyl-sulfate is: 1:(1～6).
7. the synthetic method of a kind of scheme for lacosamide according to claim 1 is characterized in that: in step (3), temperature of reaction system is :-2～10 ℃, the methylation reaction time is 1～8 hour.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892450A (en) * | 2015-06-01 | 2015-09-09 | 江苏海岸药业有限公司 | Preparation method of lacosamide |
| CN106699605A (en) * | 2015-07-21 | 2017-05-24 | 上海医药集团股份有限公司 | Methylation method of lacosamide intermediate |
| CN106811492A (en) * | 2017-01-18 | 2017-06-09 | 长兴制药股份有限公司 | A kind of preparation method of scheme for lacosamide |
| CN108084047A (en) * | 2014-07-25 | 2018-05-29 | 杭州景杰生物科技有限公司 | A kind of propionyl for preparing specificity methylates lysine ubiquitin antibody method |
| TWI634100B (en) * | 2015-09-18 | 2018-09-01 | 印度商迪比斯實驗股份有限公司 | Process for the preparation of lacosamide |
| CN114524746A (en) * | 2022-01-21 | 2022-05-24 | 河北广祥制药有限公司 | Preparation method of lacosamide crystal form |
-
2011
- 2011-11-17 CN CN 201110365255 patent/CN103113256A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084047A (en) * | 2014-07-25 | 2018-05-29 | 杭州景杰生物科技有限公司 | A kind of propionyl for preparing specificity methylates lysine ubiquitin antibody method |
| CN104892450A (en) * | 2015-06-01 | 2015-09-09 | 江苏海岸药业有限公司 | Preparation method of lacosamide |
| CN106699605A (en) * | 2015-07-21 | 2017-05-24 | 上海医药集团股份有限公司 | Methylation method of lacosamide intermediate |
| CN106699605B (en) * | 2015-07-21 | 2019-08-20 | 上海医药集团股份有限公司 | A kind of methylation method of scheme for lacosamide intermediate |
| TWI634100B (en) * | 2015-09-18 | 2018-09-01 | 印度商迪比斯實驗股份有限公司 | Process for the preparation of lacosamide |
| CN106811492A (en) * | 2017-01-18 | 2017-06-09 | 长兴制药股份有限公司 | A kind of preparation method of scheme for lacosamide |
| CN106811492B (en) * | 2017-01-18 | 2019-11-01 | 长兴制药股份有限公司 | A kind of preparation method of scheme for lacosamide |
| CN114524746A (en) * | 2022-01-21 | 2022-05-24 | 河北广祥制药有限公司 | Preparation method of lacosamide crystal form |
| CN114524746B (en) * | 2022-01-21 | 2022-11-11 | 河北广祥制药有限公司 | Preparation method of lacosamide crystal form |
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Application publication date: 20130522 |