CN102816083A - Preparation method of lacosamide - Google Patents

Preparation method of lacosamide Download PDF

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CN102816083A
CN102816083A CN2012102662587A CN201210266258A CN102816083A CN 102816083 A CN102816083 A CN 102816083A CN 2012102662587 A CN2012102662587 A CN 2012102662587A CN 201210266258 A CN201210266258 A CN 201210266258A CN 102816083 A CN102816083 A CN 102816083A
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spm927
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CN102816083B (en
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刘忠锋
张秀生
苏忆君
蔡佩珍
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Jinyao Yongguang Hebei Pharmaceutical Co ltd
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YONGGUANG PHARMACEUTICAL CO Ltd
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Abstract

The invention discloses a preparation method of (R)-2-acetamido-N-benzyl-3-methoxypropionamide (lacosamide). The method provided by the invention increases the purity and yield of lacosamide through controlling the temperature condition of each step and has the advantages of rational route, simple process operation and definite condition control.

Description

The preparation method of SPM927
Technical field
The present invention relates to a kind of preparation method who treats the SPM927 of epilepsy and neuropathic pain, be specifically related to a kind of improved preparation method who has improved the SPM927 of purity and yield.
Background technology
SPM927 (lacosamide); Chemistry (R)-2-acetamido by name-N-benzyl-3-methoxy propyl acid amides; Be the novel N-methyl D-Aspartic Acid acceptor glycine binding site point antagonist of Belgian UCB. S.A. (BE) Bruxelles Belgium exploitation, be mainly used in the assisting therapy of diabetic neuralgia and the epileptic seizures of adult epileptic's part clinically.This strain new function acidic amino acid anticonvulsant drug has dual anticonvulsant action, the alternative slow inactivation of sodium-ion channel that promotes, and the regulation and control reaction mediation albumen that subsides, thus delay even stop epileptic seizures and alleviate diabetes nerve property pain.SPM927 successively goes on the market trade(brand)name Vimpat in European Union and U.S.'s approval in August, 2008 and October.SPM927 has two kinds of formulations to get permission listing: diaphragm (50,100,150 and 200mg/ sheet), injection (10mg/ml; 20ml/ props up); Clinical study shows, to compare tolerance better with other anticonvulsive drug for it, and untoward reaction (like drowsiness and cognitive and behavior disorder) is lighter.
Announced the compound method of four kinds of SPM927 on the document: first method comprises the D-Serine is methylated, ester hydrolysis, amidation, goes protection, N-acetylize to make (R)-2-acetamido-N-benzyl-3-methoxy propyl acid amides (SPM927), total recovery about 46% through carbobenzoxy-(Cbz) protection, methyl iodide; Or methylate total recovery about 52% after the first amidation.This method reactions step is more, and isomer purity is more than 97%, and reagent cost is high, severe reaction conditions, and by product is more, must be through purified, and isomer purity does not reach requirement.Second method comprises that N-tertbutyloxycarbonyl-D-Serine methylates, generates after the isobutyl chlorocarbonate activation (R)-2-t-butoxycarbonyl amino-3-methoxyl group-N-benzyl propionic acid amide through methyl-sulfate; Make SPM927, total recovery about 5% through deprotection, N-acetylize again.This method total recovery is lower, and by product is many during preparation (R)-2-t-butoxycarbonyl amino-3-methoxyl group-N-benzyl propionic acid amide, uses chloroform: purity 97.3% behind normal hexane (1: the 9) recrystallization; But purification yield only 14.4% is unsuitable for suitability for industrialized production (Ma Yinling, Zhao Feng; Zhang Kai; Liu Leina, Du Yumin. synthesizing of SPM927. Chinese Journal of Pharmaceuticals .Chinese Journal of Pharmaceu ticals 2009,40 (9); P641-643).The third method comprises that with D-Serine and acetic anhydride generation acid amides again through the isobutyl chlorocarbonate activation, descend and the benzylamine condensation at alkaline condition (like N-methylmorpholine), silver suboxide and methyl iodide methylate and make, total recovery about 20%.This method synthetic route is simple, but reagent is expensive, is inappropriate for suitability for industrialized production, and product section racemization (about 25%).The 4th kind of method comprises that the cyclization under the catalysis of diethoxy triphenyl phosphine of D-serine methylester generates (R)-Soluol XC 100-2-methyl-formiate, and again through N-acetylize, open loop, ester hydrolysis, last and benzylamine reaction makes, and total recovery is lower than 10%.This method complex operation, cost are higher, and total recovery is low.
In sum, the existing problem of existing SPM927 preparation method mainly be the SPM927 optical purity do not reach require and yield low.
Therefore, press for a kind of improved preparation method who improves SPM927 purity and yield at present.
Summary of the invention
The purpose of this invention is to provide a kind of method for preparing SPM927.
Another object of the present invention provides the method that a kind of preparation comprises the pharmaceutical composition of SPM927.
The method for preparing SPM927 provided by the present invention may further comprise the steps:
(a) make formula I compound generation amidate action,
Figure BDA00001949575900021
Obtain the compound of formula II:
Figure BDA00001949575900031
(b) make the compound of formula II slough the compound that the R group obtains formula III:
Figure BDA00001949575900032
and
(c) make the compound generation acylation reaction of formula III obtain (R)-2-acetamido-N-benzyl-3-methoxy propyl acid amides (SPM927);
Wherein, R is the N-protected base, and the said amidate action in the step (a) carries out under-20～-15 ℃ of temperature; It is under 0～5 ℃ of temperature, to carry out that the compound that makes formula II in the step (b) is sloughed the R group; Said acylation reaction in the step (c) is under 20～25 ℃ of temperature, to carry out.
In the embodiment of first aspect, the said amidate action in the step (a) uses isobutyl chlorocarbonate as catalyzer.
In the embodiment of first aspect, the solvent that the said amidate action in the step (a) uses is selected from methylene dichloride (DCM), THF (THF), toluene, DMSO 99.8MIN. (DMSO), N, dinethylformamide (DMF), methyl alcohol and Virahol; Preferred methylene dichloride.
In the embodiment of first aspect, the said amidate action in the step (a) carries out under the condition that alkali exists.Said alkali is selected from N-methylmorpholine and triethylamine, preferred N-methylmorpholine.
In the embodiment of first aspect, said N-protected base is selected from tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz) and fluorenylmethyloxycarbonyl (Fmoc).In one embodiment, said N-protected base is carbobenzoxy-(Cbz) (Cbz), and said carbobenzoxy-(Cbz) (Cbz) is removed through the method for hydrogenation under the platinum catalysis.In another embodiment, said N-protected base is fluorenylmethyloxycarbonyl (Fmoc), and said fluorenylmethyloxycarbonyl (Fmoc) is removed through the silica gel catalyst method.In another embodiment, said N-protected base is tertbutyloxycarbonyl (Boc), and said tertbutyloxycarbonyl (Boc) is removed through the mineral acid hydrolysis method, and wherein said mineral acid is trifluoroacetic acid and hydrochloric acid, preferred hydrochloric acid.And preferred, said hydrochloric acid is concentrated hydrochloric acid.
In the embodiment of first aspect, the acylating reagent of the said acylation reaction in the step (c) is selected from diacetyl oxide, oxalyl chloride and Acetyl Chloride 98Min., preferred diacetyl oxide.
In the embodiment of first aspect, from final reacting mixture, isolate SPM927 through crystallization, wherein said crystallization is carried out in mixed solvent, and said mixed solvent is the mixture of ether and normal hexane.Preferably, the volume ratio of ether and normal hexane is 1: 2.
The method that preparation provided by the invention comprises the pharmaceutical composition of SPM927 comprises the steps:
(a) embodiment through first aspect prepare SPM927 and
(b) SPM927 and acceptable accessories are prepared into tablet or capsule.
Method of the present invention is the improvement of on the basis of second method, making; Directly with the starting raw material of (R)-2-N-Boc-amino-3-methoxypropionic acid as reaction; And reaction is chosen under the alkaline condition to be carried out; Through the temperature (the temperature control of per step reaction in the entire reaction course must be strict, and temperature head is less than 1 ℃) of strict control reaction process, product chiral purity that finally obtains and ordinary purity and yield are all high than additive method simultaneously.
Improved SPM927 preparation method of the present invention compares with existing method, the advantage below providing: the whole yield of reaction has been improved in (1); (2) eliminated the problem of racemization in the reaction, chiral purity reaches 99.1%, and ordinary purity reaches 97.8%.
Detailed Description Of The Invention
The present invention relates to a kind of improvement of compound method of SPM927 of treating epilepsy and neuropathic pain.
Concrete implementation step is following:
Figure BDA00001949575900041
Flow process 1
The characteristics of reactions step a are in the flow process 1:
1) solvent is selected
Alcohols (Virahol, ethanol, methyl alcohol etc.), halogenated alkane (methylene dichloride, chloroform etc.), pyridine furans (dihydropyridine, THF etc.), toluene, DMSO 99.8MIN. (DMSO), N; Dinethylformamide (DMF) etc. can be used as reaction solvent, and preferred exsiccant methylene dichloride is as solvent, through verification experimental verification; Methylene dichloride is as solvent; Product racemization degree has remarkable reduction, and boiling point is lower, is easy to be removed.
2) selection of temperature
The present invention begins from raw material, and all there are chirality in the midbody in each step and end product, so the temperature selection is the key of this experiment.Through repeatedly validation trial, reactions step a of the present invention is chosen under-20～-15 ℃ of temperature and carries out.
3) selection of catalysts
The preferential isobutyl chlorocarbonate of selecting is as catalyzer.
4) selection of alkali
Be reflected under the condition that alkali exists and carry out alkali such as triethylamine, diisopropyl ethyl amine, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene, saleratus and morpholine analog derivative (for example, N-methylmorpholine).The preferential N-methylmorpholine of selecting of this experiment.
The characteristics of reactions step b are in the flow process 1:
Slough N-protected base R.The method of sloughing N-protected base R has three types:
1) hydrogenation method under the platinum catalysis
When N-protected base R was carbobenzoxy-(Cbz) (Cbz), said carbobenzoxy-(Cbz) (Cbz) was removed through the method for hydrogenation under the platinum catalysis.(in the presence of Pt/C, under normal temperature and pressure and atmosphere of hydrogen, can realize taking off the purpose of Cbz.
2) mineral acid hydrolysis method
(a) trifluoroacetic acid (TFA) method
TFA can some acid nonfast blocking groups of hydrolysis, like Boc protection base, Buddha's warrior attendant carbalkoxy (Adoc) etc.
Concrete reaction mechanism is following:
(b) salt acid system
The salt acid system is with certain proportioning (about 1: 2) wiring solution-forming, room temperature reaction then with concentrated hydrochloric acid and organic solvent (like ETHYLE ACETATE).
3) silica gel catalyst method
The silica gel catalyst method is in reactant, to add toluene, after stirring, adds silica gel, reflux, and reaction is cooled to room temperature after finishing, and filters, and cleans silica gel with different solvents then, and behind the evaporate to dryness of will filtrating, further purifying gets final product.
Figure BDA00001949575900062
Silica gel catalyst method selectivity deprotection
The present invention preferably adopts the hydrolysis of concentrated hydrochloric acid method to fall N-protected base (at strong acidic condition, reaction yield is high), and temperature is controlled at 0～5 ℃.
The characteristics of reactions step c are in the flow process 1:
Reactions step c is the N-acylation reaction, and the acylating reagent of said N-acylation reaction can adopt acid anhydrides, acyl chlorides etc., such as diacetyl oxide, oxalyl chloride and Acetyl Chloride 98Min. etc.; Reaction conditions is gentle, generally under 20～25 ℃ of temperature, gets final product.
The present invention adopts diacetyl oxide, and temperature is chosen as 20～25 ℃, and the acidylate yield is 87.9%, than higher with acyl chlorides and other acylating reagent yields.
The purification step of bullion:
The present invention also comprises the purge process of product; Because racemization reaction very easily takes place in solvent SPM927, so can not adopt general recrystallization method to make with extra care, we have passed through groping under the different solvents condition in experiment; Confirm to adopt mixed solvent (ether: stirring and crystallizing normal hexane=1: 2) at last; Compare with other purification process, this method purifying products yield reaches 87.9%, and purity reaches 97.8%.
Embodiment
Embodiment 1
(R)-N-benzyl-2-N-Boc-amino-3-methoxy propyl acid amides (formula II compound) synthetic
In reaction flask, 10g (R)-2-N-Boc-amino-3-methoxypropionic acid is dissolved in the 80ml exsiccant THF temperature-15～-10 ℃ of control reaction solution; Under-10～-5 ℃ of conditions, add 5.6g isobutyl chlorocarbonate, 6.2g N-methylmorpholine; Stir 1.5h; In the time of-15～-10 ℃, in reaction flask, drip benzylamine (5.89g) solution that is dissolved in the 20ml THF then; 0.5h interior slowly be warming up to 25～30 ℃ the reaction 2.0h, whether HPLC method detection reaction complete.Use hydrochloric acid, 80ml saturated sodium bicarbonate solution and the 80ml water washing reaction solution of 80ml water, 80ml1mol/L after reaction finishes successively, tell lower floor's organic phase be concentrated into dried, oily matter; The ether that adds 80ml then: the mixed solvent of normal hexane=1: 1; Crystallization, suction filtration are stirred in the frozen water cooling; Get 9.2g white powder solid, yield 86.0%.HPLC ordinary purity 92.3%, chiral purity 81.4%.
Embodiment 2
(R)-N-benzyl-2-N-Boc-amino-3-methoxy propyl acid amides (formula II compound) synthetic
In reaction flask, 10g (R)-2-N-Boc-amino-3-methoxypropionic acid is dissolved in the 80ml exsiccant methylene dichloride temperature-15～-10 ℃ of control reaction solution; Under-10～-5 ℃ of conditions, add 5.6g isobutyl chlorocarbonate, 6.2g N-methylmorpholine; Stir 1.5h; In the time of-15～-10 ℃, in reaction flask, drip benzylamine (5.89g) solution that is dissolved in the 20ml methylene dichloride then; 0.5h interior slowly be warming up to 25～30 ℃ the reaction 2.0h, whether HPLC method detection reaction complete.Use hydrochloric acid, 80ml saturated sodium bicarbonate solution and the 80ml water washing reaction solution of 80ml water, 80ml1mol/L after reaction finishes successively, tell lower floor's organic phase be concentrated into dried, oily matter; The ether that adds 80ml then: the mixed solvent of normal hexane=1: 1; Crystallization, suction filtration are stirred in the frozen water cooling; Get 8.3g white powder solid, yield 59.0%.HPLC ordinary purity 95.3%, chiral purity 89.9%.
Embodiment 3
(R)-N-benzyl-2-N-Boc-amino-3-methoxy propyl acid amides (formula II compound) synthetic
In reaction flask; 10g (R)-2-N-Boc-amino-3-methoxypropionic acid is dissolved in the 80ml exsiccant methylene dichloride, and temperature-20～-15 ℃ of control reaction solution add 5.6g isobutyl chlorocarbonate, 6.2g N-methylmorpholine under-20～-15 ℃ of conditions; Stir 1.5h; Keep dripping in this temperature condition downhill reaction bottle benzylamine (5.89g) solution that is dissolved in the 20ml methylene dichloride then, reaction 7.0h, whether HPLC method detection reaction is complete.Use hydrochloric acid, 80ml saturated sodium bicarbonate solution and the 80ml water washing reaction solution of 80ml water, 80ml 1mol/L after reaction finishes successively, tell lower floor's organic phase be concentrated into dried, oily matter; Add the 80ml ether then: the mixed solvent of normal hexane=1: 1; Crystallization, suction filtration are stirred in the frozen water cooling; Get 7.4g white powder solid, yield 52.6%.HPLC ordinary purity 97.9%, chiral purity 99.1%.
Embodiment 4
(R)-2-amino-N-benzyl-3-methoxy propyl acid amides (formula III compound) synthetic
In reaction flask; 10g is dissolved in the methylene dichloride of 80ml with formula II compound, to 36% concentrated hydrochloric acid that wherein adds 25.0ml, keeps 25～30 ℃ of temperature; Stir about 2.0h under this temperature, TLC thin layer detect (developping agent: ethanol: normal hexane: ammoniacal liquor=1: 1: 0.1) whether reaction is accomplished.Reaction stops the back and adds 80ml water, divides water-yielding stratum, the about 15ml of sodium hydroxide solution adjust pH to 11～12 with 30%; Use methylene dichloride 60ml * 3 extractions again after adding sodium-chlor 30.0g dissolving, tell organic layer, merge organic layer; Be concentrated into dried, oily matter 7.1g, yield＞100% (bullion).HPLC ordinary purity 86.3%, chiral purity 78.3%.
Embodiment 5
(R)-2-amino-N-benzyl-3-methoxy propyl acid amides (formula III compound) synthetic
In reaction flask; 10g is dissolved in the methylene dichloride of 80ml with formula II compound; Be cooled to below 15 ℃,, keep 15～20 ℃ of temperature to wherein adding 36% concentrated hydrochloric acid 25.0ml; Stir about 3～4h under this temperature, TLC thin layer detect (developping agent: ethanol: normal hexane: ammoniacal liquor=1: 1: 0.1) whether reaction is accomplished.Reaction stops the back and adds 80ml water, divides water-yielding stratum, the about 15ml of sodium hydroxide solution adjust pH to 11～12 with 30%; Use methylene dichloride 60ml * 3 extractions again after adding sodium-chlor 30.0g dissolving, tell organic layer, merge organic layer; Be concentrated into dried, oily matter 6.9g, yield＞100% (bullion).HPLC ordinary purity 94.3%, chiral purity 85.3%.
Embodiment 6
(R)-2-amino-N-benzyl-3-methoxy propyl acid amides (formula III compound) synthetic
In reaction flask, 10g is dissolved in the methylene dichloride of 80ml with formula II compound, is cooled to below 0 ℃, to wherein adding 36% concentrated hydrochloric acid 25.0ml; Keep 0～5 ℃ of temperature, stir about 5～6h under this temperature, TLC thin layer detect (developping agent: ethanol: normal hexane: ammoniacal liquor=1: 1: 0.1) whether reaction is accomplished; Reaction stops the back and adds 80ml water, divides water-yielding stratum, the about 15ml of sodium hydroxide solution adjust pH to 11～12 with 30%; Use methylene dichloride 60ml * 3 extractions again after adding sodium-chlor 30.0g dissolving, tell organic layer, merge organic layer; Be concentrated into dried, oily matter 5.9g, yield 87.4%.HPLC ordinary purity 99.4%, chiral purity 99.8%.
Embodiment 7
(R)-2-acetamido-N-benzyl-3-methoxy propyl acid amides (SPM927) synthetic
In reaction flask, modus ponens III compound 5.0g is dissolved in methylene dichloride 50ml, stirring and dissolving; Cool to about 0 ℃, add diacetyl oxide 10.0ml, be warmed up to 20～25 ℃ under stirring; Under this temperature, stir 2.0h, TLC (developping agent: methyl alcohol: whether methylene dichloride (1: 15)) accomplish, water (20m1 * 3), 8% sodium bicarbonate aqueous solution (20m1) and water (20m1 * 3) washing successively after reacting completely by detection reaction; The pressure reducing and steaming solvent gets white solid, adds mixed solution (ether: recrystallization normal hexane=1: 2); Get SPM927 bullion 5.9g, yield 87.9%.HPLC ordinary purity 97.8%, chiral purity 99.1%.
The SPM927 that embodiment 7 makes 1The H nuclear magnetic resonance spectrum ( 1H-NMR) determination data is seen table 1.
Figure BDA00001949575900101
Table 1 SPM927 sample is in DMSO-d6 1The H-NMR data
Figure BDA00001949575900102
Embodiment 8
Can prepared SPM927 be prepared into tablet or capsule by following prescription composition and preparation method.
Prescription is formed:
Figure BDA00001949575900103
The preparation method:
1. supplementary material is sieved, subsequent use.The hydroxypropylcellulose that takes by weighing recipe quantity adds an amount of purified water wiring solution-forming, makes tackiness agent, and is subsequent use.
2. the SPM927, Microcrystalline Cellulose, the low-substituted hydroxypropyl cellulose that take by weighing recipe quantity mix, and add tackiness agent system softwood, granulation, dry, whole grain, and adding micropowder silica gel, Magnesium Stearate mix.
3. can be pressed into tablet or the can specification that specification is 50mg, 100mg, 150mg, 200mg respectively by equal proportion is the capsule of 50mg, 100mg, 150mg, 200mg.
4. can tablet be carried out dressing with film coating pre-mix dose.
Embodiment 9
Can prepared SPM927 be prepared into tablet or capsule by following prescription composition and preparation method.
Prescription is formed:
Figure BDA00001949575900111
The preparation method:
1. supplementary material is sieved, subsequent use.The HPMC that takes by weighing recipe quantity adds an amount of purified water wiring solution-forming, makes tackiness agent, and is subsequent use.
2. take by weighing SPM927, Microcrystalline Cellulose, lactose, Sodium Croscarmellose and mix, add tackiness agent system softwood, granulate, dry, whole grain, adding micropowder silica gel, Magnesium Stearate mix.
3. can be pressed into tablet or the can specification that specification is 50mg, 100mg, 150mg, 200mg respectively by equal proportion is the capsule of 50mg, 100mg, 150mg, 200mg.
4. can tablet be carried out dressing with film coating pre-mix dose.
Embodiment 10
Can prepared SPM927 be prepared into tablet or capsule by following prescription composition and preparation method.
Prescription is formed:
The preparation method:
1. supplementary material is sieved, subsequent use.The 30 POVIDONE K 30 BP/USP 30 that takes by weighing recipe quantity adds an amount of purified water wiring solution-forming, makes tackiness agent, and is subsequent use.
2. take by weighing SPM927, Microcrystalline Cellulose, N.F,USP MANNITOL, PVPP and mix, add tackiness agent system softwood, granulate, dry, whole grain, adding micropowder silica gel, Magnesium Stearate mix.
3. can be pressed into tablet or the can specification that specification is 50mg, 100mg, 150mg, 200mg respectively by equal proportion is the capsule of 50mg, 100mg, 150mg, 200mg.
4. can tablet be carried out dressing with film coating pre-mix dose.

Claims (10)

1. method for preparing SPM927 said method comprising the steps of:
(a) make formula I compound generation amidate action,
Figure FDA00001949575800011
Obtain the compound of formula II:
Figure FDA00001949575800012
(b) make the compound of formula II slough the compound that the R group obtains formula III:
Figure FDA00001949575800013
and
(c) make the compound generation acylation reaction of formula III obtain SPM927;
Wherein, R is the N-protected base, and the said amidate action in the step (a) carries out under-20～-15 ℃ of temperature; It is under 0～5 ℃ of temperature, to carry out that the compound that makes formula II in the step (b) is sloughed the R group; Said acylation reaction in the step (c) is under 20～25 ℃ of temperature, to carry out.
2. the method for claim 1, wherein the said amidate action in the step (a) uses isobutyl chlorocarbonate as catalyzer.
3. the method for claim 1, wherein the solvent that uses of the said amidate action in the step (a) is selected from methylene dichloride, THF, toluene, DMSO 99.8MIN., N, dinethylformamide, methyl alcohol and Virahol; Preferred methylene dichloride.
4. the method for claim 1, wherein the said amidate action in the step (a) carries out under the condition that alkali exists, and preferably said alkali is selected from N-methylmorpholine and triethylamine, preferred N-methylmorpholine.
5. the method for claim 1, wherein said N-protected base is selected from tertbutyloxycarbonyl, carbobenzoxy-(Cbz) and fluorenylmethyloxycarbonyl; Preferably, said N-protected base is a carbobenzoxy-(Cbz), and said carbobenzoxy-(Cbz) is removed through the method for hydrogenation under the platinum catalysis; Preferably, said N-protected base is a fluorenylmethyloxycarbonyl, and said fluorenylmethyloxycarbonyl is removed through the silica gel catalyst method; Preferably, said N-protected base is a tertbutyloxycarbonyl, and said tertbutyloxycarbonyl is removed through the mineral acid hydrolysis method, and said mineral acid is trifluoroacetic acid and hydrochloric acid, preferred hydrochloric acid, concentrated hydrochloric acid.
6. the method for claim 1, wherein the acylating reagent of the said acylation reaction in the step (c) is selected from diacetyl oxide, acetate and Acetyl Chloride 98Min., preferred diacetyl oxide.
7. like each described method in the aforementioned claim, said method also comprises through crystallization isolates SPM927 from final reacting mixture.
8. method as claimed in claim 7, wherein said crystallization is carried out in mixed solvent, and said mixed solvent is the mixture of ether and normal hexane.
9. method as claimed in claim 8, wherein the volume ratio of ether and normal hexane is 1: 2.
10. the method that comprises the pharmaceutical composition of SPM927 through following step preparation:
(a) through aforementioned claim each the preparation SPM927 and
(b) SPM927 and acceptable accessories are prepared into tablet or capsule.
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CN109010301A (en) * 2018-09-05 2018-12-18 上海上药第生化药业有限公司 A kind of lacosamide crystal form II tablet and its preparation method and application

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CN103193669A (en) * 2013-02-27 2013-07-10 南京医科大学 nNOS-Capon uncoupling compound, preparation method and application thereof
CN103193669B (en) * 2013-02-27 2014-10-01 南京医科大学 nNOS-Capon uncoupling compound, preparation method and application thereof
CN104784134A (en) * 2015-04-12 2015-07-22 石家庄四药有限公司 Lacosamidesolid preparation and preparation method thereof
CN104784134B (en) * 2015-04-12 2018-05-29 石家庄四药有限公司 A kind of scheme for lacosamide solid pharmaceutical preparation and preparation method thereof
CN109010301A (en) * 2018-09-05 2018-12-18 上海上药第生化药业有限公司 A kind of lacosamide crystal form II tablet and its preparation method and application
CN109010301B (en) * 2018-09-05 2021-01-26 上海上药第一生化药业有限公司 Lacosamide crystal form II tablet and preparation method and application thereof

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