CN107513032A - A kind of synthetic method for being used to treat the medicine and its intermediate of epilepsy - Google Patents
A kind of synthetic method for being used to treat the medicine and its intermediate of epilepsy Download PDFInfo
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- CN107513032A CN107513032A CN201710610349.0A CN201710610349A CN107513032A CN 107513032 A CN107513032 A CN 107513032A CN 201710610349 A CN201710610349 A CN 201710610349A CN 107513032 A CN107513032 A CN 107513032A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention provides a kind of synthetic method for being used to treat the medicine and its intermediate of epilepsy, belong to pharmaceutical synthesis field.The synthetic method of intermediate compound I, including：Condensation reaction is occurred into the presence of acid binding agent for formula (M1) compound and the amino-butanamides of L 2.The synthetic method of intermediate II, including：With acylating reagent acylation reaction occurs in the presence of catalyst for intermediate compound I prepared by above-mentioned synthetic method.The synthetic method of the medicine, including：Under inert gas shielding and in the presence of catalyst alkylated reaction is occurred into for the intermediate II prepared by above-mentioned synthetic method and grignard reagent.The synthetic route of this method is simple, product isolate and purify easily, production cost it is low, and the catalyst such as palladium charcoal need not be added in synthetic reaction, be advantageous to environmentally friendly and big industrial production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, in particular to a kind of medicine and its intermediate for being used to treat epilepsy
Synthetic method.
Background technology
Bu Waxitan (Brivaracetam), (2S) -2- [(4R) -2- oxo -4- propyl group -1- pyrrolidinyls] butyramide
(i.e. Bu Waxitan), it is a kind of new anti-epileptic class medicine, it has high affinity with prominent vesicle protein 2A parts, can
Suppress neuronal voltagedependent sodium channel.The Belgian excellent when ratio (UCB) of pharmacy giant is in 2015 respectively to FDA and European medicine
Bu Waxitan NDA and listing license application is submitted by product management board (EMA), and granted.Bu Waxitan is after Zuo Yila
It is western it is smooth after the very good third generation anti-epileptic class medicine of a prospect.
So far, Bu Waxitan preparation method has a variety of, and the patent such as CN106432030, CN106588741 is equal
Report a variety of Bu Waxitan synthetic method, but the purification procedures difficulty of the complex synthetic route of these methods, product
Need greatly and in synthetic reaction to add the catalyst such as palladium charcoal mostly, be unfavorable for environmentally friendly and big industrial production.
The content of the invention
The first object of the present invention is to provide a kind of intermediate compound I for being used to treat the medicine of epilepsy and intermediate II
Synthetic method, this method reaction scheme is simple, high income, and resulting product be easy to obtain purity by chiral separation it is higher
Monomeric compound.
The second object of the present invention is to provide a kind of synthetic method for being used to treat the medicine of epilepsy, the conjunction of this method
Into route it is simple, it is product isolate and purify easily, production cost it is low, and the catalysis such as palladium charcoal need not be added in synthetic reaction
Agent, be advantageous to environmentally friendly and big industrial production.
In order to realize the above-mentioned purpose of the present invention, spy uses following technical scheme：
A kind of synthetic method for being used to treat the intermediate compound I of the medicine of epilepsy, it includes：By formula (M1) compound and L-2-
Condensation reaction occurs in the presence of acid binding agent for amino-butanamide；
The structural formula of intermediate compound I is：
The structural formula of formula (M1) compound is：
In formula, X=Cl, Br or I；R=alkoxies, halogen, amido or-O- acyl groups.
A kind of synthetic method for being used to treat the intermediate II of the medicine of epilepsy, it includes：It is prepared by above-mentioned synthetic method
Intermediate compound I and acylating reagent acylation reaction occurs in the presence of catalyst；
The structural formula of intermediate II is：
In formula, R=sulfonyls or acyl group.
A kind of synthetic method for being used to treat the medicine of epilepsy, it includes：Intermediate II prepared by above-mentioned synthetic method
Alkylated reaction occurs under inert gas shielding and in the presence of catalyst with grignard reagent.
Compared with prior art, the beneficial effect of present disclosure includes：
The synthetic method of the intermediate compound I for the medicine that present disclosure provides, utilizes formula (M1) compound and L-2- amino fourths
The two raw materials of acid amides, the precursor compound to form Bu Waxitan, i.e. intermediate compound I can be only cyclized by single step reaction, reacted
Route is simple, high income, and resulting product is easy to obtain the higher monomeric compound of purity by chiral separation.
The synthetic method of the intermediate II for the medicine that present disclosure provides, on the basis of intermediate compound I, tried using acylated
Acylated hydroxy in intermediate compound I is improved the reactivity of hydroxyl, using the intermediate II, can easily realize Bu Waxitan by agent
Synthesis.
The synthetic method for the medicine that present disclosure provides, i.e. Bu Waxitan synthetic method, with formula (M1) compound with
The two chiral precursors of L-2- amino-butanamides are initial feed, first synthetic intermediate I；Acylating reagent is recycled by intermediate
Acylated hydroxy on I, obtains intermediate II；The alkylated reaction of grignard reagent is then recycled, obtains target product Bu Waxi
It is smooth.The synthetic route of this method is simple, product isolate and purify easily, production cost it is low, and need not in synthetic reaction
The catalyst such as palladium charcoal are added, are advantageous to environmentally friendly and big industrial production.
Embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the present invention.It is unreceipted specific in embodiment
Condition person, the condition suggested according to normal condition or manufacturer are carried out.Agents useful for same or the unreceipted production firm person of instrument, it is
The conventional products that can be obtained by commercially available purchase.
Present embodiment provides a kind of synthetic method for being used to treat the intermediate compound I of the medicine of epilepsy, and it includes：By formula
(M1) with L-2- amino-butanamides condensation reaction occurs in the presence of acid binding agent for compound；
The structural formula of intermediate compound I is：
The structural formula of formula (M1) compound is：
In formula, X=Cl, Br or I；R=alkoxies, halogen, amino, imino group or-O- acyl groups.
The reaction equation of the condensation reaction is：
In the condensation reaction, the N not being joined directly together with carbonyl on reactant M2 is negative electricity subbase group, goes attack to react
Carbonyl carbon on thing M1 and the carbon being connected with halogen, occur amine ester exchange reaction and nucleophilic substitution, condensation and cyclization shape respectively
Into the five-membered ring in intermediate compound I.
Further, acid binding agent includes organic base and inorganic base, inorganic base include potassium hydroxide, sodium hydroxide, potassium carbonate,
Sodium carbonate；Organic base includes triethylamine, pyridine and ethylenediamine.Acid binding agent is added, the hydrogen halides for contributing to neutralization reaction to generate, is carried
The yield of high intermediate compound I.
Further, alkoxy includes any one in ethyoxyl, methoxyl group, propoxyl group and butoxy；Halogen includes
Chlorine or bromine.
When R=amidos, M1 can be：Deng.
When R=-O- acyl groups, M1 is
Further, the reaction dissolvent of the condensation reaction is weakly polar organic solvent, for example, dichloromethane, chloroform,
Ethyl acetate, tetrahydrofuran etc..
Further, the reaction condition of the condensation reaction includes：Under the state that is heated to reflux, 3~5h is reacted；Or it is
4h.That is, heating maintains the reflux for reaction dissolvent during the course of the reaction, reacts 3~5h.
Further, the isolation and purification method of intermediate compound I includes：Confirm raw material after completion of the reaction, washed with reaction dissolvent
Twice, organic phase is dried, and is concentrated into no cut, is crossed post purifying, is obtained product (S) -2- ((S) -4- hydroxyl -2- oxo-pyrrolidines -1-
Base) butyramide, i.e. intermediate compound I.
Present embodiment provides a kind of synthetic method for being used to treat the intermediate II of the medicine of epilepsy, and it includes：Will be by
With acylating reagent acylation reaction occurs in the presence of catalyst for intermediate compound I prepared by above-mentioned synthetic method；
The structural formula of intermediate II is：
In formula, R=sulfonyls or acyl group.
The reaction equation of the acylation reaction is：
Further, acylating reagent includes any one in sulfonic acid chloride, carboxylic acid halides, acid anhydrides and carboxylic acid.
When acylating reagent is to include sulfonic acid chloride, for example it is paratoluensulfonyl chloride (TSCl), the structure of intermediate II is：
Wherein TSFor p-toluenesulfonyl.
When acylating reagent is acyl chlorides, for example it is formyl chloride, the structure of intermediate II is：
Further, catalyst includes pyridine, N, N- dimethyl -4-aminopyridine or DMF, enters one
Step, catalyst is pyridine.Adding the effect of such catalyst is, during the course of the reaction, catalyst and intermediate compound I form centre
Body I salt, for example the pyridiniujm intermediate of intermediate compound I is formed, the reactivity of the salt of the intermediate compound I is more than intermediate compound I, thus
It is smoothed out the reaction.
Further, the reaction dissolvent of the acylation reaction is weakly polar organic solvent, for example, dichloromethane, chloroform,
Ethyl acetate, tetrahydrofuran etc..
Further, the reaction condition of the acylation reaction is：Reaction temperature is -10~5 DEG C, and the reaction time is 2~3h；Or
Person, reaction temperature are -4 DEG C, reaction time 2.5h.
Further, the purification process of intermediate II includes：Will be molten with organic solvent after the reaction solution concentration for reacting gained
Solution, is preferably dissolved with reaction dissolvent, and regulation pH value the crystallization at -10~10 DEG C, obtains intermediate II to acidity.Optionally, instead
After should terminating, reaction solution is quenched with frozen water, concentration is dried after layering, residue dissolves with organic solvent, such as with ethyl acetate,
PH value is adjusted to 4~5, at 5 DEG C crystallization.Dissolving residue can also use other organic solvents, such as chloroform, petroleum ether etc..
Also a kind of synthetic method for being used to treat the medicine of epilepsy of present embodiment, it includes：It is prepared by above-mentioned synthetic method
Intermediate II and grignard reagent alkylated reaction occurs under inert gas shielding and in the presence of catalyst.
The reaction equation of the alkylated reaction is：
Optionally, grignard reagent includes propyl group magnesium bromide, propyl group magnesium chloride, propyl group iodinase；Optionally, grignard reagent is
Propyl group magnesium bromide.
Further, catalyst includes any one in KBr, KI, sodium iodide and sodium bromide.Optionally,
Catalyst is KBr.
Further, the reaction dissolvent of the alkylated reaction is weakly polar organic solvent, such as dichloromethane, three chloromethanes
Alkane, ethyl acetate, tetrahydrofuran etc..
Further, the reaction condition of the alkylated reaction is：2~3h of insulation reaction at 0~10 DEG C, or for 3
2.2~2.8h of insulation reaction at~8 DEG C, or be insulation reaction 2.5h at 5 DEG C.
Further, the purification process of the medicine (i.e. compound III) includes：Confirm after completion of the reaction, reaction solution is slow
Add in frozen water, be layered, dry, concentration, residue re-crystallizing in ethyl acetate, obtain white powder solid.
The feature and performance of the present invention are described in further detail with reference to embodiments：
Embodiment 1
The present embodiment provides a kind of synthetic method for the intermediate compound I for preparing the medicine for treating epilepsy, and it includes：
S (-) -4- chloro-3-hydroxyls ethyl butyrate (100g) and L-2- amino-butanamides are starting material (61.3g), with two
Chloromethanes is solvent, adds acid binding agent KOH (33.0g), is stirred at reflux under state, insulation reaction 4 hours.
Reaction equation is：
Confirm raw material after completion of the reaction, the dichloromethane that 200mL is added in reaction solution is washed twice, and organic phase is dried, dense
No cut is reduced to, post purifying is crossed, obtains product intermediate compound I, i.e. (S) -2- ((S) -4- hydroxyl -2- oxo-pyrrolidine -1- bases) butyryl
Amine, 96.1g, purity 98.2%, yield 86%.
Embodiment 2
The present embodiment provides a kind of synthetic method for the intermediate compound I for preparing the medicine for treating epilepsy, and it includes：
S (-) -4- chloro-3-hydroxyls methyl butyrate (100g) and L-2- amino-butanamides are starting material (61.3g), with three
Chloromethanes is solvent, adds acid binding agent triethylamine (59.5g), is stirred at reflux under state, insulation reaction 3 hours.
Confirm raw material after completion of the reaction, the dichloromethane that 250mL is added in reaction solution is washed twice, and organic phase is dried, dense
No cut is reduced to, post purifying is crossed, obtains product intermediate compound I, i.e. (S) -2- ((S) -4- hydroxyl -2- oxo-pyrrolidine -1- bases) butyryl
Amine, 96.4g, purity 98.7%, yield 86.4%.
Embodiment 3
The present embodiment provides a kind of synthetic method for the intermediate compound I for preparing the medicine for treating epilepsy, and it includes：
S (-) -4- chloro-3-hydroxyls ethyl butyrate (100g) and L-2- amino-butanamides are starting material (61.3g), with three
Chloromethanes is solvent, adds acid binding agent potassium carbonate (81.3g), is stirred at reflux under state, insulation reaction 4 hours.
Confirm raw material after completion of the reaction, the dichloromethane that 150mL is added in reaction solution is washed twice, and organic phase is dried, dense
No cut is reduced to, post purifying is crossed, obtains product intermediate compound I, i.e. (S) -2- ((S) -4- hydroxyl -2- oxo-pyrrolidine -1- bases) butyryl
Amine, 96.3g, purity 98.4%, yield 86.3%.
Embodiment 4
The present embodiment provides a kind of synthetic method for the intermediate II for preparing the medicine for treating epilepsy, and it includes：
The method synthetic intermediate I provided according to embodiment 1~3.
800mL DCM is added in reaction bulb, 90g intermediate Is, stirring and dissolving, pyridine 7.0g is added, is added dropwise at -5 DEG C
101.5g TSCl+200mL DCM mixed solutions, keeping temperature are not higher than -10~-5 DEG C, react 3 hours.
Reaction equation is：
After reaction terminates, frozen water is quenched, and is layered, and dries, concentration.Residue ethyl acetate room-temperature dissolution, acid adjustment to PH
4~5, in 5 DEG C of crystallizations 3 hours, filter, dry, obtain intermediate II 137.2g, purity 99.1%, yield 75.4%.
Embodiment 5
The present embodiment provides a kind of synthetic method for the intermediate II for preparing the medicine for treating epilepsy, and it includes：
The method synthetic intermediate I provided according to embodiment 1~3.
800mL DCM is added in reaction bulb, 90g intermediate Is, stirring and dissolving, adds DMF
7.0g, 101.5g T are added dropwise at 0 DEG CSCl+200mL DCM mixed solutions, 0~5 DEG C is maintained the temperature at, reacted 2 hours.
After reaction terminates, frozen water is quenched, and is layered, and dries, concentration.Residue ethyl acetate room-temperature dissolution, acid adjustment to PH
4~5, crystallization 3 hours at -10 DEG C, filter, dry, obtain intermediate II 137.4g, purity 99.0%, yield 75.8%.
Embodiment 6
The present embodiment provides a kind of synthetic method for the intermediate II for preparing the medicine for treating epilepsy, and it includes：
The method synthetic intermediate I provided according to embodiment 1~3.
800mL DCM is added in reaction bulb, 90g intermediate Is, stirring and dissolving, adds N, N- dimethyl -4- amino pyrroles
Pyridine 7.0g, 101.5g T are added dropwise at -2 DEG CSCl+200mL DCM mixed solutions, -5~0 DEG C is maintained the temperature at, reaction 2.5 is small
When.
After reaction terminates, frozen water is quenched, and is layered, and dries, concentration.Residue ethyl acetate room-temperature dissolution, acid adjustment to PH
4~5, crystallization 2 hours at 10 DEG C, filter, dry, obtain intermediate II 137.0g, purity 99.4%, yield 75.3%.
Embodiment 7
The present embodiment provides a kind of synthetic method for preparing the medicine for treating epilepsy, and it includes：
- a of method synthetic intermediate II provided according to embodiment 4.
Input 1000mLDCM is solvent, under nitrogen protection, 130g intermediate IIs, 41g KBr is added at 5 DEG C, control is anti-
Temperature is answered, propyl group magnesium bromide is slowly added dropwise.After being added dropwise, in 5 DEG C of insulation reactions 2.5 hours.
Reaction equation is：
Confirm after completion of the reaction, reaction solution is slowly added in frozen water, be layered, dry, concentration, residue ethyl acetate
Recrystallization, obtain white powder solid (being Bu Waxitan), 54.6g, purity 99.4%, yield 74.8%.
Embodiment 8
The present embodiment provides a kind of synthetic method for preparing the medicine for treating epilepsy, and it includes：
The method synthetic intermediate II provided according to embodiment 4~6.
It is solvent to put into 1000mL DCM, under nitrogen protection, 130g intermediate IIs, 25.6g KCl, control is added at 10 DEG C
Reaction temperature processed, propyl group magnesium chloride is slowly added dropwise.After being added dropwise, in 10 DEG C of insulation reactions 2 hours.
Confirm after completion of the reaction, reaction solution is slowly added in frozen water, be layered, dry, concentration, residue ethyl acetate
Recrystallization, obtain white powder solid (being Bu Waxitan), 54.3g, purity 99.2%, yield 74.5%.
Embodiment 9
The present embodiment provides a kind of synthetic method for preparing the medicine for treating epilepsy, and it includes：
The method synthetic intermediate II provided according to embodiment 4~6.
It is solvent to put into 1000mL DCM, under nitrogen protection, 130g intermediate IIs, 41g KBr, control is added at 0 DEG C
Reaction temperature, propyl group magnesium bromide is slowly added dropwise.After being added dropwise, in 0 DEG C of insulation reaction 3 hours.
Confirm after completion of the reaction, reaction solution is slowly added in frozen water, be layered, dry, concentration, residue ethyl acetate
Recrystallization, obtain white powder solid (being Bu Waxitan), 54.4g, purity 99.3%, yield 74.6%.
In summary, the synthetic method for the medicine that present embodiment provides, i.e. Bu Waxitan synthetic method, with formula (M1)
The two chiral precursors are initial feed, first synthetic intermediate I to compound with L-2- amino-butanamides；Recycle acylating reagent
By the acylated hydroxy in intermediate compound I, intermediate II is obtained；The alkylated reaction of grignard reagent is then recycled, obtains target production
Thing Bu Waxitan.The synthetic route of this method is simple, product isolate and purify easily, production cost it is low, and in synthetic reaction
In need not add the catalyst such as palladium charcoal, be advantageous to environmentally friendly and big industrial production.
Although illustrate and describing the present invention with specific embodiment, but will be appreciated that without departing substantially from the present invention's
Many other change and modification can be made in the case of spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of synthetic method for being used to treat the intermediate compound I of the medicine of epilepsy, it is characterised in that it includes：Formula (M1) is changed
With L-2- amino-butanamides condensation reaction occurs in the presence of acid binding agent for compound；
The structural formula of the intermediate compound I is：
The structural formula of formula (M1) compound is：
In formula, X=Cl, Br or I；R=alkoxies, halogen, amido or-O- acyl groups.
2. the synthetic method of intermediate compound I according to claim 1, it is characterised in that the acid binding agent include potassium hydroxide,
Any of sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, pyridine and ethylenediamine.
3. the synthetic method of intermediate compound I according to claim 1, it is characterised in that the alkoxy includes ethyoxyl, first
Any one in epoxide, propoxyl group and butoxy.
4. the synthetic method of intermediate compound I according to claim 1, it is characterised in that the reaction condition of the condensation reaction
Including：Under the state that is heated to reflux, 3~5h is reacted.
5. a kind of synthetic method for being used to treat the intermediate II of the medicine of epilepsy, it is characterised in that it includes：It will be wanted by right
Intermediate compound I prepared by the synthetic method described in 1~4 any one is asked to occur with acylating reagent in the presence of catalyst acylated anti-
Should；
The structural formula of the intermediate II is：
In formula, R=sulfonyls or acyl group.
6. the synthetic method of intermediate II according to claim 5, it is characterised in that the acylating reagent includes sulphonyl
Any one in chlorine, carboxylic acid halides, acid anhydrides and carboxylic acid.
7. the synthetic method of intermediate II according to claim 5, it is characterised in that the catalyst includes pyridine, N,
N- dimethyl -4-aminopyridine or DMF.
8. the synthetic method of intermediate II according to claim 5, it is characterised in that the purification process of the intermediate II
Including：It will be dissolved after the reaction solution concentration for reacting gained with organic solvent, regulation pH value is to acidity, the crystallization at -10~10 DEG C.
9. a kind of synthetic method for being used to treat the medicine of epilepsy, it is characterised in that it includes：Will be any by claim 5~8
Intermediate II prepared by the synthetic method described in is sent out with grignard reagent under inert gas shielding and in the presence of catalyst
Raw alkylated reaction.
10. the synthetic method according to claim 9 for being used to treat the medicine of epilepsy, it is characterised in that the catalyst
Including any one in KBr, KI, sodium iodide and sodium bromide.
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Cited By (1)
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| WO2019242192A1 (en) * | 2018-06-20 | 2019-12-26 | 上海朴颐化学科技有限公司 | Brivaracetam intermediate, preparation method therefor, and preparation method for brivaracetam |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019242192A1 (en) * | 2018-06-20 | 2019-12-26 | 上海朴颐化学科技有限公司 | Brivaracetam intermediate, preparation method therefor, and preparation method for brivaracetam |
| US11518741B2 (en) | 2018-06-20 | 2022-12-06 | Shanghai Puyi Chemical Co., Ltd. | Brivaracetam intermediate, preparation method therefor, and preparation method for brivaracetam |
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