CN107641087A - A kind of preparation method for industrializing scheme for lacosamide - Google Patents
A kind of preparation method for industrializing scheme for lacosamide Download PDFInfo
- Publication number
- CN107641087A CN107641087A CN201710404594.6A CN201710404594A CN107641087A CN 107641087 A CN107641087 A CN 107641087A CN 201710404594 A CN201710404594 A CN 201710404594A CN 107641087 A CN107641087 A CN 107641087A
- Authority
- CN
- China
- Prior art keywords
- lacosamide
- acetamido
- scheme
- acetyl
- ser
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- HVAAHUDGWQAAOJ-UHFFFAOYSA-N CCNCc1ccccc1 Chemical compound CCNCc1ccccc1 HVAAHUDGWQAAOJ-UHFFFAOYSA-N 0.000 description 1
- QUTGXAIWZAMYEM-UHFFFAOYSA-N NCCOC1CCCC1 Chemical compound NCCOC1CCCC1 QUTGXAIWZAMYEM-UHFFFAOYSA-N 0.000 description 1
Abstract
A kind of preparation method for industrializing scheme for lacosamide.By D serine esters metaplasia into D serine methyl ester hydrochlorides；By D serine methyl ester hydrochlorides and excess acetyl chloride generation N acetyl D serine methylesters；The N acetyl D serine methylesters and benzylamine are reacted to obtain the hydroxypropanamide of (R) 2 acetamido N benzyls 3；The hydroxypropanamide of (R) 2 acetamido N benzyls 3 obtains the methoxypropionamide of (R) 2 acetamido N benzyls 3 with being reacted under methyl tosylate alkalescence condition by described in.Each step reaction condition of the invention is more gentle, and raw material are easy to get, and not using highly toxic reagent, meets the green chemical concept of safety and environmental protection, is relatively adapted to industrialization amplification.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and specifically, the present invention relates to a kind of preparation side for industrializing scheme for lacosamide
Method.
Background technology
Scheme for lacosamide (Lacosamide), Chinese chemical name：(R) -2- Acetamido-N-benzyls -3- methoxypropionamides,
Molecular formula C13H18N2O3, molecular weight 250.29, it is that the third generation of Belgian UCB Pharma SA's exploitation treats epilepsy and god
Medicine through property pain.Scheme for lacosamide binding mode is different from other commercially available antiepileptics at present：This product regulation sodium leads to
Road activity, and other commercially available antiepileptic block sodium channels.Sodium channel contributes to the nervous system of Nerve cell communication in regulation
Activity plays vital effect.Sometimes, sodium channel abnormal movement can excessively cause epileptic attack.Thus, scheme for lacosamide
Binding mode is considered as the hyperactivity hyperkinesia for reducing sodium channel, and the activity of this regulation nerve cell can control the breaking-out of epilepsy.Face
Bed before research also show, scheme for lacosamide be incorporated into reaction of exhaustion regulatory protein -2 (CRMP-2, be mainly distributed on neuron differentiation and
Control the phosphoprotein in the nervous system of axon undue growth), it is unique anti-epileptic listed with CRMP-2 interactions
Medicine.
Scheme for lacosamide (Lacosamide) structural formula is as follows：
The content of the invention
The invention provides a kind of reaction condition is gentle, the preparation method of the higher industrialization scheme for lacosamide of yield, this hair
Bright each step reaction condition is more gentle, and raw material are easy to get, and not using highly toxic reagent, meets the Green Chemistry of safety and environmental protection
Theory, relatively it is adapted to industrialization amplification.
To achieve the above object, the present invention uses following technical scheme：
A kind of preparation method for industrializing scheme for lacosamide, this method comprise the following steps：
Step 1.D- serine methyl ester hydrochlorides (LKXA-01)
D-Ser is dissolved into absolute methanol and is cooled to -5~0 DEG C, nitrogen protection, thionyl chloride is added dropwise, drips off
After be warmed to room temperature stirring reaction 2 hours, then proceed to be warming up to backflow, be stirred at reflux overnight.After reaction completely, solvent under reduced pressure rotation
Dry, ethyl acetate mashing washing filters to obtain D-Ser methyl ester hydrochloride；
Step 2.N- acetyl-D-Ser methyl esters (LKXA-02)
Taking D-Ser methyl ester hydrochloride to add dichloromethane reduces temperature to 0 DEG C, adds triethylamine, continues to reduce temperature
To -10-0 DEG C, -10-0 DEG C of chloroacetic chloride temperature control is added dropwise, reaction solution keeping temperature stirs 3 hours, washing layering, takes organic layer to dry
It is concentrated to give N- acetyl-D-Ser methyl esters；
Step 3. (R) -2- Acetamido-N-benzyl -3- hydroxypropanamides (LKXA-03)
Taking under N- acetyl-D-Ser methyl esters and benzylamine nitrogen protects, rise temperature is to 65 DEG C, stirring reaction 12 hours,
Decompression boils off excessive benzylamine, and residue is cooled to 50 DEG C, adds tetrahydrofuran, and stirring is cooled to room temperature, has substantial amounts of solid to analyse
Go out, filter out solid, depressurize 40 DEG C of drying, obtain (R) -2- Acetamido-N-benzyl -3- hydroxypropanamides；
Step 4. scheme for lacosamide (Lacosamide)
Take (R) -2- Acetamido-N-benzyl -3- hydroxypropanamides, tetrabutyl ammonium sulfate, methyl tosylate, tetrahydrochysene
Under furans, the protection of 20% sodium hydrate aqueous solution nitrogen, reaction solution is heated to 35 DEG C, and then insulated and stirred will up to 4 hours
It is cooled to room temperature and adds 28% ammoniacal liquor, continues stirring 1 hour, hydrochloric acid adjusts pH value, and decompression boils off tetrahydrofuran, residue for neutrality
It is diluted with water, dichloromethane extraction, organic phase is simultaneously steamed to small size, and substantial amounts of solid, filtering are separated out with isopropyl acetate stirring
And washed with isopropyl acetate, the 40 DEG C of dryings of filter cake vacuum, obtain scheme for lacosamide (Lacosamide).
Each step reaction condition of the invention is more gentle, and raw material are easy to get, and not using highly toxic reagent, meet safety collar
The green chemical concept of guarantor, relatively it is adapted to industrialization amplification.
Embodiment
In order to which the present invention is apparent to understand, with reference to specific embodiment, the invention will be further described, to help
Understand present disclosure.
Embodiment one
Step 1.D- serine methyl ester hydrochlorides (LKXA-01)
105.09g D-Sers are dissolved into 1.5L absolute methanols and are cooled to -5~0 DEG C, nitrogen protection, are added dropwise
178.46g thionyl chlorides, stirring reaction is warmed to room temperature after dripping off 2 hours, then proceedes to be warming up to backflow, be stirred at reflux overnight,
After reaction completely, solvent under reduced pressure is spin-dried for, and ethyl acetate mashing washing filters to obtain white solid D-Ser methyl ester hydrochloride 219g,
Yield 93%.
Step 2.N- acetyl-D-Ser methyl esters (LKXA-02)
Taking 100g D-Sers methyl ester hydrochloride to add 500ml dichloromethane reduces temperature to 0 DEG C, adds the second of 136.6g tri-
Amine, continuing to reduce temperature to -10-0 DEG C, -10-0 DEG C of 53.06g chloroacetic chlorides temperature control is added dropwise, reaction solution keeping temperature stirs 3 hours,
Washing layering, takes organic layer to dry to obtain grease N- acetyl-D-Ser methyl esters 93.1g, yield 90%.
Step 3. (R) -2- Acetamido-N-benzyl -3- hydroxypropanamides (LKXA-03)
Take under 100g N- acetyl-D-Ser methyl esters and the protection of 332g benzylamines nitrogen, for rise temperature to 65 DEG C, stirring is anti-
Answer 12 hours, decompression boils off excessive benzylamine, and residue is cooled to 50 DEG C, adds 50ml tetrahydrofurans, and stirring is cooled to room temperature, had
Substantial amounts of solid separates out, and filters out solid, depressurizes 40 DEG C of drying, obtains (R) -2- Acetamido-N-benzyl -3- hydroxypropanamides
123g, yield 83.1%.
Step 4. scheme for lacosamide (Lacosamide)
148g (R) -2- Acetamido-N-benzyl -3- hydroxypropanamides, 7.4g tetrabutyl ammonium sulfate are taken, to 350g toluene
Under methylmesylate, 740ml tetrahydrofurans, the protection of the sodium hydrate aqueous solution nitrogen of 440g 20%, reaction solution is heated to 35 DEG C,
And then insulated and stirred was cooled to room temperature and adds 165g28% ammoniacal liquor up to 4 hours, continue stirring 1 hour, hydrochloric acid tune pH value is
Neutrality, decompression boil off tetrahydrofuran, and residue is diluted with water, dichloromethane extraction, and organic phase is simultaneously steamed to small size, different with acetic acid
Propyl ester stirring separates out substantial amounts of solid, filters and is washed with isopropyl acetate, the 40 DEG C of dryings of filter cake vacuum, obtains scheme for lacosamide
(Lacosamide) 115g, yield 73%.
Synthetic route is as follows：
General principle, principal character and the advantages of the present invention of the present invention, the technology of the industry has been shown and described above
Personnel under the premise without departing from the spirit and scope of the present invention, can also it will be appreciated that the present invention is not limited to the above embodiments
There are various changes and modifications, these changes and improvement all fall within the protetion scope of the claimed invention.
Claims (1)
1. a kind of preparation method for industrializing scheme for lacosamide, it is characterised in that this method comprises the following steps：
Step 1.D- serine methyl ester hydrochlorides (LKXA-01)
D-Ser is dissolved into absolute methanol and is cooled to -5~0 DEG C, nitrogen protection, thionyl chloride is added dropwise, is risen after dripping off
To reaction 2 hours is stirred at room temperature, then proceed to be warming up to backflow, be stirred at reflux overnight.After reaction completely, solvent under reduced pressure is spin-dried for,
Ethyl acetate mashing washing filters to obtain D-Ser methyl ester hydrochloride；
Step 2.N- acetyl-D-Ser methyl esters (LKXA-02)
Taking D-Ser methyl ester hydrochloride to add dichloromethane reduces temperature to 0 DEG C, adds triethylamine, continues to reduce temperature to -10-
0 DEG C, -10-0 DEG C of chloroacetic chloride temperature control is added dropwise, reaction solution keeping temperature stirs 3 hours, washing layering, takes organic layer to dry and is concentrated to give
N- acetyl-D-Ser methyl esters；
Step 3. (R) -2- Acetamido-N-benzyl -3- hydroxypropanamides (LKXA-03)
Take under N- acetyl-D-Ser methyl esters and the protection of benzylamine nitrogen, rise temperature stirring reaction 12 hours, depressurizes to 65 DEG C
Excessive benzylamine is boiled off, residue is cooled to 50 DEG C, adds tetrahydrofuran, and stirring is cooled to room temperature, has substantial amounts of solid to separate out, mistake
Solid is filtered out, 40 DEG C of drying is depressurized, obtains (R) -2- Acetamido-N-benzyl -3- hydroxypropanamides；
Step 4. scheme for lacosamide (Lacosamide)
Take (R) -2- Acetamido-N-benzyl -3- hydroxypropanamides, tetrabutyl ammonium sulfate, methyl tosylate, tetrahydrochysene furan
Mutter, under the protection of 20% sodium hydrate aqueous solution nitrogen, reaction solution is heated to 35 DEG C, and insulated and stirred is up to 4 hours, then by it
It is cooled to room temperature and adds 28% ammoniacal liquor, continues stirring 1 hour, hydrochloric acid adjusts pH value, and decompression boils off tetrahydrofuran, and residue adds for neutrality
Water is diluted, dichloromethane extraction, and organic phase is simultaneously steamed to small size, separates out substantial amounts of solid with isopropyl acetate stirring, filtering is simultaneously
Washed with isopropyl acetate, the 40 DEG C of dryings of filter cake vacuum, obtain scheme for lacosamide (Lacosamide).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710404594.6A CN107641087A (en) | 2017-06-01 | 2017-06-01 | A kind of preparation method for industrializing scheme for lacosamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710404594.6A CN107641087A (en) | 2017-06-01 | 2017-06-01 | A kind of preparation method for industrializing scheme for lacosamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107641087A true CN107641087A (en) | 2018-01-30 |
Family
ID=61110295
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710404594.6A Pending CN107641087A (en) | 2017-06-01 | 2017-06-01 | A kind of preparation method for industrializing scheme for lacosamide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107641087A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108558690A (en) * | 2018-03-28 | 2018-09-21 | 浙江海正药业股份有限公司 | The crystal form and preparation method thereof of seromycin carboxylate hydrochloride |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102822140A (en) * | 2010-01-29 | 2012-12-12 | 意优特克股份公司 | Process for the synthesis of lacosamide |
| CN103102342A (en) * | 2011-11-14 | 2013-05-15 | 广东东阳光药业有限公司 | Aminoquinazoline derivative, salts thereof and application method |
| CN105541968A (en) * | 2016-01-27 | 2016-05-04 | 安婕妤化妆品科技股份有限公司 | Preparation method and application of pentapeptide |
| CN105777464A (en) * | 2014-12-26 | 2016-07-20 | 中国科学院上海药物研究所 | Hydroxamic acid derivative, and preparation method and application thereof |
| CN106543018A (en) * | 2015-09-18 | 2017-03-29 | 迪比斯实验股份有限公司 | The method for preparing scheme for lacosamide |
| CN106565586A (en) * | 2016-11-09 | 2017-04-19 | 中国农业大学 | Naphthalenesulfonamide type compound, preparation method of naphthalenesulfonamide type compound and application of naphthalenesulfonamide type compound to adjustment of plant growth activity |
-
2017
- 2017-06-01 CN CN201710404594.6A patent/CN107641087A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102822140A (en) * | 2010-01-29 | 2012-12-12 | 意优特克股份公司 | Process for the synthesis of lacosamide |
| CN103102342A (en) * | 2011-11-14 | 2013-05-15 | 广东东阳光药业有限公司 | Aminoquinazoline derivative, salts thereof and application method |
| CN105777464A (en) * | 2014-12-26 | 2016-07-20 | 中国科学院上海药物研究所 | Hydroxamic acid derivative, and preparation method and application thereof |
| CN106543018A (en) * | 2015-09-18 | 2017-03-29 | 迪比斯实验股份有限公司 | The method for preparing scheme for lacosamide |
| CN105541968A (en) * | 2016-01-27 | 2016-05-04 | 安婕妤化妆品科技股份有限公司 | Preparation method and application of pentapeptide |
| CN106565586A (en) * | 2016-11-09 | 2017-04-19 | 中国农业大学 | Naphthalenesulfonamide type compound, preparation method of naphthalenesulfonamide type compound and application of naphthalenesulfonamide type compound to adjustment of plant growth activity |
Non-Patent Citations (1)
| Title |
|---|
| TANG LIN-JUN等: ""Study on Synthesis of (R)-2,2-Dimethyl-3-(tert-butoxycarbonyl)-4-ethynylox-azolidine"", 《ADVANCED MATERIALS RESEARCH》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108558690A (en) * | 2018-03-28 | 2018-09-21 | 浙江海正药业股份有限公司 | The crystal form and preparation method thereof of seromycin carboxylate hydrochloride |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105061224B (en) | Synthetic method of L-2-aminobutanol | |
| CN101941969B (en) | Preparation method of moxifloxacin hydrochloride | |
| CN106459014B (en) | The preparation method of Lei Dipawei and its derivative and the midbody compound for being used to prepare Lei Dipawei | |
| CN104974060A (en) | Method for preparing sodium, 8-(2-hydroxybenzamido)octanoate | |
| CN101723855B (en) | Method for synthesizing (7-methoxy-1-naphthyl) acetonitrile | |
| CN105085373B (en) | A kind of purification process to Apremilast product | |
| CN107793325A (en) | A kind of new method for preparing synthetic capsaicin | |
| CN104530033B (en) | A kind of preparation technology new method of Arotinolol Hydrochlorid | |
| CN101798271B (en) | Method for preparing (+/-)-norepinephrine | |
| CN102993038B (en) | Preparation method of itopride hydrochloride | |
| CN107641087A (en) | A kind of preparation method for industrializing scheme for lacosamide | |
| CN105085484B (en) | A kind of preparation method of Vonoprazan fumarate | |
| CN112645869A (en) | Preparation method of chlorpheniramine maleate intermediate | |
| CN109369460A (en) | The synthetic method of one kind (2S) -2-N- fluorenylmethyloxycarbonyl amino -2,4- dimethyl valeric acid | |
| CN103044468B (en) | Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid | |
| CN105884833A (en) | Preparation method and antineoplastic activity of novel ruthenium complex containing 4,4'-dibromo-2,2'-dipyridyl | |
| CN106632280A (en) | Method for preparing alfuzosin hydrochloride | |
| CN105237406A (en) | Synthesis method of (R)-(-)-1-methyl-3-amphetamine | |
| CN105523957B (en) | The method that one kettle way prepares scheme for lacosamide | |
| CN106810546A (en) | A kind of umeclidinium compound | |
| CN104876856B (en) | A kind of method that Split Method prepares (R) (+) 3 amino piperidine dihydrochloride | |
| CN102786466B (en) | Synthetic method of chiral Salan ligand | |
| CN107434811A (en) | A kind of method of glufosinate-ammonium purifying | |
| CN104478802A (en) | Process for synthesizing 3,3-pentamethylene glutarimide | |
| CN107337628B (en) | Method for preparing levetiracetam |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180130 |