CN106432030A - Preparation method of brivaracetam - Google Patents
Preparation method of brivaracetam Download PDFInfo
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- CN106432030A CN106432030A CN201510648574.4A CN201510648574A CN106432030A CN 106432030 A CN106432030 A CN 106432030A CN 201510648574 A CN201510648574 A CN 201510648574A CN 106432030 A CN106432030 A CN 106432030A
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- 0 CCC[C@](C1)CN(*(*CC)C(N)=O)C1=O Chemical compound CCC[C@](C1)CN(*(*CC)C(N)=O)C1=O 0.000 description 6
- VOMAAWRLZIQVIT-ZBHICJROSA-N CCC[C@@H](CO1)C(C(O)=O)C1=O Chemical compound CCC[C@@H](CO1)C(C(O)=O)C1=O VOMAAWRLZIQVIT-ZBHICJROSA-N 0.000 description 1
- NVTUTJMZAZZKAZ-ZCFIWIBFSA-N CCC[C@H](C1)COC1=O Chemical compound CCC[C@H](C1)COC1=O NVTUTJMZAZZKAZ-ZCFIWIBFSA-N 0.000 description 1
- NYIXDCWAFHWQTI-ZCFIWIBFSA-N CCC[C@H](CC(Cl)=O)CCl Chemical compound CCC[C@H](CC(Cl)=O)CCl NYIXDCWAFHWQTI-ZCFIWIBFSA-N 0.000 description 1
- HNNJFUDLLWOVKZ-VKHMYHEASA-N CC[C@@H](C(N)=O)N Chemical compound CC[C@@H](C(N)=O)N HNNJFUDLLWOVKZ-VKHMYHEASA-N 0.000 description 1
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- 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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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for synthesizing brivaracetam. Raw materials used in the method are available and inexpensive, a preparation process avoids appearance of chiral isomers difficult to separate, purification means such as column chromatography purification and the like adverse to industrial amplification production is avoided, a synthesis process is not involved with expensive and toxic heavy metal and chiral ligands, and a product brivaracetam with high quality and high optical purity can be obtained.
Description
Technical field
The application is related to pharmaceutical synthesis field, in particular it relates to a kind of method of synthesis Bu Waxitan.
Background technology
Epilepsy is the commonly encountered diseases of nervous system, and the sickness rate in crowd is 0.6%～1.1%, wherein
60%～70% patient still can show effect when taking anti-epilepsy agent, leads to a part of patient voluntarily to stop
Drug therapy.There is about more than 6,000,000 epileptic in China at present, newly sends out epileptic 65 every year
Ten thousand～700,000, about 25% is intractable epilepsy.Although the diagnosis and treatment of current epilepsy achieve very big entering
Exhibition, but the quantity for the treatment of of intractable epilepsy is increasing.Broad sense intractable epilepsy refers to use mesh
Front antiepileptic (AEDs) Canonical management is it is impossible to terminating its outbreak or having been confirmed it is difficult by clinical
The epilepsy controlled and epilepsy syndromes.
Bu Waxitan (Brivaracetam) is the synaptic vesicle proteins 2A of a new high-affinity
Part, can inhibitory neuron voltage gated sodium channel, for treating intractable epilepsy partial seizures.
The II phase of Bu Waxitan, III clinical trial phase all has preferable curative effect.The mainly bad thing of Bu Waxitan
The incidence rate of part is similar to the incidence rate of placebo group, is slight fatigue to moderate, headache, nose
Pharyngitis, nausea, drowsiness and dizzy.No patient because of adverse events therapy discontinued.Result shows Bu Wa
Western smooth the auxiliary treatment age be 16～65 years old intractable epilepsy partial seizures patient in be to have
Effect and toleration is good.In general, Bu Waxitan is a prospect after levetiracetam
Very good third generation epilepsy class medicine.
So far, the domestic patent with regard to Bu Waxitan synthesis have not been reported.External Patents
Report is also few, such as patent US 6, and 784,197, US 7,629,474, US 8,957,226, US
8,338,621, US 8,076,493 and its Patents report the synthesis of Bu Waxitan, wherein US
6,784,197, US 7,629,474 report following synthetic route：
US 8,957,226 (embodiment 1,3) and US 8,338,621 (embodiment 4,11) report with
Under synthetic route：
Kenda etc. (Joumal of Medicinal Chemistry, 2004,47,530) reports following conjunction
Become route：
Above-mentioned several route had not all built the chiral centre of n-pro-pyl on butyrolactam, but final
Obtain the Bu Waxitan of optical purity, the profit of raw material by the method for Chiral HPLC purification in product
With and uneconomical.
Accordingly, there exist the demand to the simple and cost-effective method preparing Bu Waxitan, to obtain
The Bu Waxitan of high-optical-purity.
Content of the invention
The purpose of the application is to provide a kind of method of synthesis Formula VII Bu Waxitan, for existing skill
Art defect, provides a kind of low cost, and yield is good, the Bu Waxi of the strong suitable industrialized production of controllability
Smooth new method.
The application provides a kind of method of synthesis Formula VII Bu Waxitan, and methods described comprises the steps：
Wherein, R is C1-20Alkyl is it is preferable that R is methyl, ethyl, propyl group, pi-allyl, just
Butyl, isobutyl group, isopropyl, n-pentyl, n-hexyl, the tert-butyl group or benzyl, more preferably R are
Ethyl.
In some embodiments, R can be methyl, ethyl, propyl group, pi-allyl, positive fourth
Base, isobutyl group, isopropyl, n-pentyl, n-hexyl, the tert-butyl group or benzyl.
Those skilled in the art is it will be further understood that synthetic route in accordance with the above, this area
Technical staff be fully able to according to its technology general knowledge and routine techniquess means, by reasonable selection ability
Raw material known to domain and synthetic method are come the product required for obtaining.
In a detailed embodiment, the reaction condition of each reactions steps can be：
Formula II compound is prepared by compound of formula I：
At a temperature of -78 DEG C to 200 DEG C, in aprotic organic solvent, make compound of formula I and second
Alkylmetal reagent reaction preparation Formula II compound, the use molar equivalent of wherein ethyl metal reagent is permissible
Between 1-5；Preferably, described ethyl metal reagent can be selected from ethylmagnesium bromide, ethylmercury chloride
One of magnesium, diethyl zinc, ethyl-lithium and lead diethide or more kinds of；It is highly preferred that described second
Alkylmetal reagent can be used in combination with Hydro-Giene (Water Science)., Cupricin. or anhydrous zinc chloride, iodine in reaction
The use molar equivalent of the cuprous, Cupricin. of change or anhydrous zinc chloride is between 0.01-2；Preferably,
Described aprotic organic solvent can selected from oxolane (THF), methyltetrahydrofuran, toluene, two
One of chloromethanes, ether and methyl tertiary butyl ether(MTBE) or more kinds of；
By Formula II preparation of compounds of formula III compound：
In the mixture with water for the organic solvent, in the presence of alkali, in 0 DEG C -200 DEG C of temperature model
Formula II compound experience hydrolysis are made to obtain formula III compound, the wherein use mole of alkali in enclosing
Equivalent is between 0.01-10；Preferably, described alkali is selected from Lithium hydrate, potassium hydroxide or hydroxide
One of sodium or more kinds of, described organic solvent can selected from oxolane, methyltetrahydrofuran,
One of toluene, dichloromethane, ether and methyl tertiary butyl ether(MTBE) or more kinds of；
If or, R contains unsaturated part, Formula II compound can be made to remove R by metal catalytic
Group.
By formula III preparation of compounds of formula IV compound：
In solvent-free or organic solvent, in a heated condition, within the temperature range of 50 DEG C -200 DEG C
Formula III compound is made to experience decarboxylic reaction to obtain formula IV compound；Preferably, described organic solvent
Can be selected from oxolane, methyltetrahydrofuran, toluene, dichloromethane, ether and methyl tertbutyl
One of ether or more kinds of；
Formula II compound obtains formula III compound via hydrolysis, then decarboxylation synthesis formula IV chemical combination
Thing can effectively improve yield and the purity of product, and the complexity operating is not significantly increased.
By Formula II preparation of compounds of formula IV compound：
In the mixture with water for the aprotic polar organic solvent, in the presence of salt or alkali, at 50 DEG C
Formula II compound experience takes off ester group is made to be reacted to give formula IV compound within the temperature range of -200 DEG C,
The use molar equivalent of wherein salt or alkali is between 0.01-10；Preferably, described salt be selected from lithium chloride,
One of sodium chloride, potassium chloride, magnesium chloride and lithium bromide or more kinds of, described alkali is selected from hydroxide
One of lithium, potassium hydroxide or sodium hydroxide or more kinds of, described aprotic polar organic solvent choosing
From N-Methyl pyrrolidone, DMF, dimethyl sulfoxide, sulfolane and 4- methyl -2-
One of amylalcohol or more kinds of；
Formula IV compound can as reactant and solvent under conditions of High Temperature High Pressure with (S) -2-
Amino-butanamide or its corresponding salt, or obtain corresponding conjunction to (S) -2- amino n-butyl alcohol direct reaction
The Bu Waxitan becoming or its key intermediate.
By formula IV preparation of compounds of formula V compound：
Wherein at a temperature of 0 DEG C to backflow it is preferable that at a temperature of between 55 DEG C -80 DEG C,
ZnCl2In the presence of, so that thionyl chloride is reacted with formula IV compound：Preferably, thionyl chloride is simultaneously
The use molar equivalent of the solvent as reaction and thionyl chloride between 1-50, it is highly preferred that described
The use molar equivalent of thionyl chloride is between 1-5.
To prepare the change of Formula IV by the reaction of Formula V compound and (S) -2- amino butanamide or its salt
Compound：
Wherein in the basic conditions, in organic solvent, at a temperature of -50 DEG C -50 DEG C, make Formula V
Compound and (S) -2- amino butanamide or its reactant salt, to prepare Formula IV compound, are wherein used for
The use molar equivalent of alkali forming alkalescence condition between 1-5, (S) -2- amino-butanamide or its salt
Use molar equivalent between 0.5-5；Preferably, described alkali is selected from triethylamine, diisopropyl second
Base amine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide,
Potassium tert-butoxide, lithium diisopropylamine, two (trimethyl silicon substrate) Lithamide .s or two (trimethyl silicon substrates)
One of Sodamide. or more kinds of, described organic solvent be selected from oxolane, methyltetrahydrofuran,
Ether, acetone, butanone, dichloromethane, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane, methanol, ethanol,
One of isopropanol, DMF, N-Methyl pyrrolidone, dimethyl sulfoxide or more
Multiple.Preferably, using inorganic weak bases such as potassium carbonate, acetone, acetonitrile, DMF
Deng the preferable solvent of water solublity as reaction dissolvent；Improve used alkali and reaction medium, effectively
Inhibit the racemization of (S) -2- amino group.Employ water-miscible organic solvent as reaction medium letter
Change post-processing operation, post processing purification can effectively improve the optical purity of product, and with high yield
Obtain highly purified Formula IV compound.
The method that Bu Waxitan is prepared by Formula IV compound：
Wherein in the basic conditions, in organic solvent, at a temperature of -78 DEG C -100 DEG C, make formula
There is itself ring closure reaction preparation Formula VII Bu Waxitan in VI, be wherein used for forming the alkali of alkalescence condition
Using molar equivalent between 1-5；Preferably, described alkali be selected from triethylamine, diisopropyl ethyl amine,
Pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, tertiary fourth
Potassium alcoholate, lithium diisopropylamine, two (trimethyl silicon substrate) Lithamide .s or two (trimethyl silicon substrate) ammonia
One of base sodium or more kinds of, organic solvent be selected from oxolane, methyltetrahydrofuran, ether,
Acetone, butanone, dichloromethane, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane, methanol, ethanol, isopropyl
One of alcohol, DMF, N-Methyl pyrrolidone, dimethyl sulfoxide or more kinds of.
Preferably, using inorganic bases such as potassium hydroxide, N-Methyl pyrrolidone, dimethyl sulfoxide, N, N- bis-
The aprotic polar solvents such as methylformamide are as reaction dissolvent；Improve used alkali and reaction is situated between
Matter, effectively inhibits the racemization of (S) -2- amino group, and obtains highly purified formula with high yield
VII compound Bu Waxitan.
Prepare the side of Bu Waxitan by the reaction of Formula V compound and (S) -2- amino butanamide or its salt
Method：
Wherein in the basic conditions, in organic solvent, at a temperature of -50 DEG C -50 DEG C, make Formula V
Compound to prepare Formula VII compound Bu Waxitan with (S) -2- amino butanamide or its reactant salt,
Wherein it is used for forming the use molar equivalent of the alkali of alkalescence condition between 1-10, (S) -2- amino fourth
The use molar equivalent of amide or its salt is between 0.5-5；Preferably, described alkali be selected from sodium hydroxide,
Potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, diisopropyl ammonia
One of base lithium, two (trimethyl silicon substrate) Lithamide .s or two (trimethyl silicon substrate) Sodamide. or more
Multiple, described organic solvent be selected from oxolane, methyltetrahydrofuran, ether, acetone, butanone,
Dichloromethane, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane, methanol, ethanol, isopropanol, N, N- diformazan
One of base Methanamide, N-Methyl pyrrolidone, dimethyl sulfoxide or more kinds of.Be necessary
In the case of, need to add the carrying out that phase transfer catalyst promotes reaction, wherein the making of phase transfer catalyst
With equivalent in 0-1.Between；Preferably, described phase transfer catalyst be selected from tetrabutylammonium chloride, four
Butylammonium bromide, tetrabutylammonium iodide, one of Polyethylene Glycol or more kinds of.Preferably, adopt
The inorganic bases such as potassium hydroxide, dichloromethane, acetonitrile, acetone equal solvent are as reaction dissolvent；Poly- second two
Alcohol 400, as phase transfer catalyst, improves used alkali, phase transfer catalyst and reaction medium,
Effectively inhibit the racemization of (S) -2- amino group, a step efficiently, high yield obtain highly purified
Formula VII compound Bu Waxitan.
In a specific exemplary embodiment, methods described may include steps of：
Wherein, R is C1-20Alkyl is it is preferable that R is ethyl.
In above or other embodiment, compound of formula I can be commercial products, such as super happyization
Learn the product of article No. SP-13711.
In above or other embodiment, compound of formula I also can be prepared in the following manner：
Wherein, R is C1-20Alkyl, wherein reaction temperature are 0 DEG C -100 DEG C, and the use mole of alkali is worked as
Between 1 and 3, the use molar equivalent of compound IX is between 0.5-3 for amount；Preferably, described alkali
Selected from one of metallic sodium, metallic potassium or more kinds of, it is highly preferred that described metallic sodium be Feldalat NM,
Sodium ethylate or sodium tert-butoxide, described metallic potassium is potassium tert-butoxide；Described organic solvent is selected from ethanol, first
One of alcohol, propanol, isopropanol or more kinds of.
Compared with prior art, the method for synthesizing Bu Waxitan of the application has following benefit：
1st, raw material is easy to get and cheap.
2nd, the isolating and purifying easily in this embodiment it is not even necessary to purification of intermediate and product, you can directly series connection
Next step preparation Bu Waxitan and its similar compound are done in reaction, simple to operate.
3rd, due to constructing the chiral centre of the n-pro-pyl on butyrolactam at the very start, can obtain
The Bu Waxitan of high-optical-purity, need not expensive poisonous heavy metal and chiral ligand.
4th, avoided by method described herein preparation Bu Waxitan and be difficult to detached chiral photo-isomerisation
The appearance of body, it is to avoid column chromatography purification etc. is unfavorable for the means of purification of industry's enlarging production, synthesizes
Journey is not related to expensive poisonous heavy metal and chiral ligand, obtains the product of high-quality, high-optical-purity
(in four kinds of optical isomers, Bu Waxitan ratio is more than 99.5%), remaining single contaminant efficient liquid phase
Peak area is less than 0.1%, split without using expensive Chiral HPLC method, it is to avoid chiral separation
Waste for raw material.Prepare the gross production rate about 50% of Bu Waxitan by compound of formula I, higher than existing
Disconnecting route.
Specific embodiment
Below by embodiment, presently filed embodiment to be described, those skilled in the art should recognize
Know, the enforcement technology that these specific embodiments only indicate that to reach the purpose of the application and select
Scheme, is not the restriction to technical scheme.According to teachings of the present application, in conjunction with prior art to this
The improvement of application technical scheme is obvious, belongs to the scope of the application protection.
The implementation condition adopting in embodiment can be done according to specific requirement and adjust further, not marked
Implementation condition is usually the condition in normal experiment.
Wherein, the chemical reagent used in the examples below is commercial chemical reagent.
In an exemplary embodiment of the present invention embodiment, Bu Waxitan to be synthesized using following route：
In said synthesis route, those skilled in the art can also make to said synthesis route
Change, for example, change specific reaction condition or the synthesis road to a certain step or a few step as needed
Line adjusts, these without departing from the present invention flesh and blood change made all in this Shen
In protection domain please.
Embodiment 1 prepare compound 3
Feldalat NM (2.0kg, 37.03mol) is added dissolving in 44.5kg dehydrated alcohol complete,
If adding diethyl malonate (6.0kg, 37.46mol) at outer warm 10 DEG C.Stir at this temperature
Mix 10 minutes, system is warmed to room temperature, be slowly added to (R)-epoxychloropropane in reaction system
(ee ＞ 99%) (3.3kg, 35.67mol) (purchased from pacifying resistance to Jilin Chemical), finishes, system flows back
Under the conditions of react 2 hours, stopped reaction, system is cooled to room temperature, is spin-dried for solvent, adds 19.03
Kg water, is extracted 2 times with 12kg ethyl acetate with 17.0kg.Merge organic faciess, anhydrous sulfur
Sour sodium is dried, and drying finishes, and filters, filtrate is spin-dried for, and obtains colourless liquid through vacuum distillation, obtains
Compound 3, yield 50%.The chiral HPLC (ee 98.5%) of compound 3
The nuclear magnetic data of compound 3 is as follows：1H NMR (400MHz, CDCl3)：δ 4.33 (1H,
Dd), 4.23 (2H, q), 4.16 (1H, d), 2.73-2.75 (1H, m), 2.05 (1H, dd), 1.35 (1H, t),
1.28 (3H, t).
Embodiment 2 prepare compound 4
The 2- methyltetrahydrofuran solution of ethyl grignard reagent is added in reactor
(1.29mol/kg, 2.44kg, 3.14mol), controls interior temperature to be -20--30 DEG C, by CuI
(108.3g, 0.57mol) adds in reaction system, stirs 30min, then drips in reaction bulb
Plus as described in Example 1 method be obtained compound 3 (434g, 2.55mol) 2- is dried
Methyltetrahydrofuran solution.Completion of dropping, after stirring 30 minutes at this temperature, uses saturation
Ammonium chloride is quenched reaction, and point liquid obtains the 2- methyltetrahydrofuran solution of compound 4, yield：64%.
Using column chromatography purification (developing solvent polarity：Petrol ether/ethyl acetate=10/1) obtain pure
The nuclear magnetic data of the compound 4 after change is as follows：1H NMR (400MHz, CDCl3)δ4.52
(1H, dd), 4.27 (2H, q), 3.92 (1H, dd), 3.23 (1H, d), 2.96-3.03 (1H, m),
1.49-1.56 (2H, m), 1.27-1.35 (5H, m), 0.95 (3H, t).
Using column chromatography purification (developing solvent polarity：Petrol ether/ethyl acetate=10/1) obtain pure
The specific rotatory power of the compound 4 after change is：[α]23 D=+22.6 (C=10, CHCl3)
Embodiment 3 prepare compound 4
The 2- methyltetrahydrofuran solution (1.29 of ethyl grignard reagent is added in reaction bulb
Kg/mol, 63.51g, 81.93mmol), reaction bulb is placed in low-temp reaction bath, controls interior
Temperature is -20--30 DEG C, and CuI (2.22g, 11.70mol) is being added stirring 0.5 in reaction bulb
Hour, then to the compound 3 that method is obtained as described in Example 1 of Deca in reaction bulb (10.0g,
58.52mmol) 2- methyltetrahydrofuran solution is dried.Completion of dropping, stirs at this temperature
After mixing 30 minutes, reaction is quenched with saturated ammonium chloride, point liquid obtains the 2- methyl four of compound 4
Hydrogen tetrahydrofuran solution, yield：87%.
Using column chromatography purification (developing solvent polarity：Petrol ether/ethyl acetate=10/1) obtain pure
The nuclear magnetic data of the compound 4 after change is as follows：1H NMR (400MHz, CDCl3)δ4.52
(1H, dd), 4.27 (2H, q), 3.92 (1H, dd), 3.23 (1H, d), 2.96-3.03 (1H, m),
1.49-1.56 (2H, m), 1.27-1.35 (5H, m), 0.95 (3H, t).
Using column chromatography purification (developing solvent polarity：Petrol ether/ethyl acetate=10/1) obtain pure
The specific rotatory power of the compound 4 after change is：[α]23 D=+22.6 (C=10, CHCl3)
Embodiment 4 prepare compound 5
The 2- methyltetrahydrofuran solution of the compound 4 that method as described in Example 3 is obtained,
Add NaOH/H2O (255g/640mL), system reacts point liquid after 2h at room temperature, obtains
Aqueous phase is washed once with 1L ethyl acetate, and it is 1 that enriching hydrochloric acid adjusts pH, plus 1L 2- methyl tetrahydrochysene
Furan is extracted twice, and merges organic faciess, concentrates, and obtains compound 5, receive after steaming using toluene set
Rate 99%
Using column chromatography purification (developing solvent：Ethyl acetate) obtain compound 5 after purification
Nuclear magnetic data is as follows：1H NMR (400MHz, CDCl3) δ 10.57 (1H, brs), δ 4.54
(1H, dd), 3.95 (1H, dd), 3.30 (1H, d), 2.96-3.03 (1H, m), 1.39-1.76 (2H, m),
1.27-1.35 (2H, m), 0.95 (3H, t).
Embodiment 5 prepare compound 6
The compound 5 that method as described in Example 4 is obtained adds in reaction bulb, if temperature outward
120 DEG C, it is down to room temperature after reaction 2h, vacuum distillation obtains compound 6, yield：99%.
The nuclear magnetic data of compound 6 is as follows：1H NMR (400MHz, CDCl3) δ 4.42 (1H,
Dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40-1.47 (2H, m),
1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H, t).
The specific rotatory power of compound 6 is：[α]23 D=+3.9 (C=10, CHCl3)
Embodiment 6 prepare compound 6
The compound 5 that method as described in Example 4 is obtained adds in reaction bulb, adds 2vol
Toluene, if 120 DEG C of temperature outward, is down to room temperature after reaction 8h, vacuum distillation obtains compound 6, receives
Rate：95%.
The nuclear magnetic data of compound 6 is as follows：1H NMR (400MHz, CDCl3) δ 4.42 (1H,
Dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40-1.47 (2H, m),
1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H, t).
The specific rotatory power of compound 6 is：[α]23 D=+3.9 (C=10, CHCl3)
Embodiment 7 prepare compound 7
Anhydrous zinc chloride (10.6g, 0.078mol) is added compound 6 (100g, 0.78mol)
Reaction bulb in, then will in 200mL thionyl chloride add reaction.Reaction bulb is placed in 85 DEG C
React in oil bath, treat GC detection no starting material left, stopped reaction, system is cooled to room temperature,
Back-out thionyl chloride, then the compound 7 of slightly yellow liquid, yield 79.7% is obtained through vacuum distillation.
The nuclear magnetic data of compound 7 is as follows：1H NMR (400MHz, CDCl3)：1H
NMR (400MHz, CDCl3)：δ 3.67 (1H, dd), 3.59 (1H, dd), 2.58 (1H, dd), 2.40
(1H, dd), 2.20-2.31 (1H, m), 1.25-1.53 (4H, m), 0.93 (3H, t).
The specific rotatory power of compound 7 is：[α]23 D=+2.9 (C=10, CHCl3)
Embodiment 8 prepare compound 8
By (S) -2- amino-butanamide hydrochloride (10g, 72.5mmol) (purchased from Beijing coupling
Science and Technology Ltd.) add 150mL to be dried in acetonitrile, addition potassium carbonate (25g,
181.3mmol), at 0 DEG C after stirring 30 minutes, be added dropwise over compound 7 (14.6g,
79.71mmol), completion of dropping, is stirred at room temperature to TLC detection no starting material left.It is spin-dried for,
Add 150mL dichloromethane, 150mL water, 10mL ethanol, extraction separates organic faciess, use
100mL dichloromethane extracts once, merges organic faciess, anhydrous sodium sulfate drying, drying finishes,
Filter, filtrate is concentrated to give compound 8, yield 96%.
It is further purified using recrystallization and obtain highly purified compound 8.Compound after purification
8 nuclear magnetic data is as follows：1H NMR (400MHz, CDCl3) δ 6.20-6.45 (2H, m), 5.69
(1H, brs), 4.46 (1H, dd), 3.61 (2H, d), 2.23-2.42 (3H, m), 1.85-1.97 (1H, m),
1.62-1.75 (1H, m), 1.23-1.53 (4H, m), 0.97 (3H, t), 0.91 (3H, t).
The specific rotatory power of compound 8 is：[α]25 D=-23.7 (C=3, CH3OH)
Embodiment 9 prepares Bu Waxitan compound 9
The compound 8 (2.0g, 8mmol) that method as described in Example 8 is obtained, adds dry
In dry DMF 6mL, potassium hydroxide (670mg, 12mmol) is added in reaction bulb in five times.
System is reacted to HPLC detection no starting material left at -15 to -10 DEG C, and 1N hydrochloric acid reacts,
Add 12vol saturated aqueous common salt, methyl tertiary butyl ether(MTBE) extracts four times, merge organic faciess, saturation
NaCl solution washed once, anhydrous sodium sulfate drying, filters, and filtrate is concentrated to give product, gained
Solid is Bu Waxitan, yield 95%, can obtain high-purity product through further recrystallization purifying,
The product of chiral HPLC ＞ 99.5%.
The nuclear magnetic data of compound 9 is as follows：1H NMR (400MHz, CDCl3) δ 6.45 (brs,
1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd,
1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m,
1H), 1.25-1.48 (m, 4H), 0.80-0.95 (m, 6H).
Embodiment 10 prepares Bu Waxitan compound 9
By (S) -2- amino-butanamide hydrochloride (8.0g, 58mmol) (purchased from Beijing coupling section
Skill company limited) add in 120mL dry methylene chloride, addition PEG400 (3.5g,
8.7mmol), at being down to -10 DEG C stirring 30 minutes after, be dividedly in some parts KOH (17.9g,
320mmol), it is added dropwise over compound 7 (11.7g, 64mmol) therebetween, completion of dropping, -2 DEG C
Stir to TLC detection no starting material left.Semi-saturation ammonium chloride is quenched reaction, and extraction has separated
Machine phase, is extracted twice with 40mL dichloromethane, merging organic faciess, anhydrous sodium sulfate drying,
Filter, filtrate is concentrated to give product, and products therefrom is Bu Waxitan, and yield 92%, through entering one
Step recrystallization purifying can obtain high-purity product, the product of chiral HPLC ＞ 99%.
The nuclear magnetic data of compound 9 is as follows：1H NMR (400MHz, CDCl3) δ 6.45 (brs,
1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd,
1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m,
1H), 1.25-1.48 (m, 4H), 0.80-0.95 (m, 6H).
Embodiment 11 prepares Bu Waxitan compound 9
By (S) -2- amino-butanamide hydrochloride (2.5g, 18mmol) (purchased from Beijing coupling section
Skill company limited) add in 40mL dry methylene chloride, addition tetrabutyl ammonium bromide (1.16g,
3.6mmol), at being down to -10 DEG C stirring 30 minutes after, be dividedly in some parts KOH (4.53g,
81mmol), it is added dropwise over compound 7 (3.66g, 20mmol) therebetween, completion of dropping, -2 DEG C
Stir to TLC detection no starting material left.Semi-saturation ammonium chloride is quenched reaction, and extraction has separated
Machine phase, is extracted twice with 40mL dichloromethane, merging organic faciess, anhydrous sodium sulfate drying,
Filter, filtrate is concentrated to give product, and products therefrom is Bu Waxitan, and yield 83%, through entering one
Step recrystallization purifying can obtain high-purity product, the product of chiral HPLC ＞ 99%.
The nuclear magnetic data of compound 9 is as follows：1H NMR (400MHz, CDCl3) δ 6.45 (brs,
1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd,
1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m,
1H), 1.25-1.48 (m, 4H), 0.80-0.95 (m, 6H).
Embodiment 12 prepares Bu Waxitan compound 9
The compound 8 (2.5g, 10mmol) that method as described in Example 8 is obtained, adds dry
In dry dichloromethane 20mL, add tetrabutyl ammonium bromide (161mg, 0.5mmol) by hydrogen
Potassium oxide (730mg, 13mmol) adds in reaction bulb at twice.System is anti-at -15 to -10 DEG C
Should be to HPLC detection no starting material left, saturated ammonium chloride is quenched reaction, dichloromethane extraction three
Secondary, merge organic faciess, anhydrous sodium sulfate drying, filter, filtrate is concentrated to give product, gained produces
Thing is Bu Waxitan, yield 68%, can obtain high-purity product through further recrystallization purifying,
The product of chiral HPLC ＞ 99.5%.
The nuclear magnetic data of compound 9 is as follows：1H NMR (400MHz, CDCl3) δ 6.45 (brs,
1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd,
1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m,
1H), 1.25-1.48 (m, 4H), 0.80-0.95 (m, 6H).
Embodiment 13 prepares Bu Waxitan compound 9
The compound 8 (100mg, 0.4mmol) that method as described in Example 8 is obtained, plus
Enter in dry methylene chloride 1mL, add PEG400 (24mg, 0.06mmol) by hydrogen-oxygen
Change sodium (32mg, 0.8mmol) to add in reaction bulb.System is reacted to HPLC at -15 to -10 DEG C
Detection no starting material left, saturated ammonium chloride is quenched reaction, and dichloromethane extracts three times, is associated with
Machine phase, anhydrous sodium sulfate drying, filters, filtrate is concentrated to give product, products therefrom is cloth watt
Western smooth, yield 87%.
The nuclear magnetic data of compound 9 is as follows：1H NMR (400MHz, CDCl3) δ 6.45 (brs,
1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd,
1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m,
1H), 1.25-1.48 (m, 4H), 0.80-0.95 (m, 6H).
Embodiment 14 prepares Bu Waxitan compound 9
The compound 8 (100mg, 0.4mmol) that method as described in Example 8 is obtained, plus
Enter to be dried in acetonitrile 1mL, add PEG400 (24mg, 0.06mmol) by potassium hydroxide
(45mg, 0.8mmol) adds in reaction bulb.System is reacted to HPLC inspection at -15 to -10 DEG C
Survey no starting material left, saturated ammonium chloride is quenched reaction, is spin-dried for organic solvent, extracted with dichloromethane
Take three times, merge organic faciess, anhydrous sodium sulfate drying, filter, filtrate is concentrated to give product, institute
Obtain product and be Bu Waxitan, yield 86%.
The nuclear magnetic data of compound 9 is as follows：1H NMR (400MHz, CDCl3) δ 6.45 (brs,
1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd,
1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m,
1H), 1.25-1.48 (m, 4H), 0.80-0.95 (m, 6H).
Embodiment 14 prepares Bu Waxitan compound 9
The compound 8 (100mg, 0.4mmol) that method as described in Example 8 is obtained, plus
Enter in dry acetone 1mL, add PEG400 (24mg, 0.06mmol) by potassium hydroxide
(45mg, 0.8mmol) adds in reaction bulb.System is reacted to HPLC inspection at -15 to -10 DEG C
Survey no starting material left, saturated ammonium chloride is quenched reaction, is spin-dried for organic solvent, extracted with dichloromethane
Take three times, merge organic faciess, anhydrous sodium sulfate drying, filter, filtrate is concentrated to give product, institute
Obtain product and be Bu Waxitan, yield 90%.
The nuclear magnetic data of compound 9 is as follows：1H NMR (400MHz, CDCl3) δ 6.45 (brs,
1H), 5.80 (brs, 1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd,
1H), 2.25-2.40 (m, 1H), 2.05 (dd, 1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m,
1H), 1.25-1.48 (m, 4H), 0.80-0.95 (m, 6H).
Embodiment 15 prepare compound 6
CuI (9.5g, 50mol) is added in 100mL dry THF, reaction bulb is placed in -30 DEG C
Low-temp reaction bath in, in reaction bulb add ethyl grignard reagent THF solution (1.0M,
300mL, 300mmol) stir 1 hour, then to Deca in reaction bulb as described in Example 1
The dry THF solution of the compound 3 (20g, 117mmol) that method is obtained.Completion of dropping,
After stirring 30 minutes at this temperature, it is to slowly warm up to -15 DEG C.It is quenched instead with saturated ammonium chloride
Should, add 1L water, extracted three times with 1L ethyl acetate, merge organic faciess, anhydrous sodium sulfate
It is dried, drying finishes, filters, filtrate is concentrated to give compound 4.This compound 4 is added
DMSO/H2O (400mL/20mL), LiCl (14.7g, 350mmol) is added in reaction bulb.
System, after 140 DEG C of reaction 18h, is poured in 400mL water, uses 400mL ethyl acetate
Extraction three times, merges organic faciess, and saturation NaCl solution washed once, anhydrous sodium sulfate drying,
Filter, filtrate is concentrated to give crude product, and vacuum distillation obtains compound 6, colourless liquid, yield 50%.
The nuclear magnetic data of compound 6 is as follows：1H NMR (400MHz, CDCl3) δ 4.42 (1H,
Dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40-1.47 (2H, m),
1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H, t).
The specific rotatory power of compound 6 is：[α]23 D=+3.9 (C=10, CHCl3)
Embodiment 16 prepare compound 5
The 2- methyltetrahydrofuran solution (1.36 of ethyl grignard reagent is added in reaction bulb
Mol/kg, 64.85g, 88.2mmol), reaction bulb is placed in low-temp reaction bath, controls interior
Temperature is -20--30 DEG C, and CuI (2.24g, 11.79mmol) is being added stirring 0.5 in reaction bulb
Hour, then to the compound 3 that method is obtained as described in Example 1 of Deca in reaction bulb (10.0g,
58.52mmol) 2- methyltetrahydrofuran (10mL) solution is dried.Add 60mL 3N
HCl/water solution is quenched reaction.This mixed liquor was heated to reflux after 24 hours, standing point liquid,
Obtain the 2- methyltetrahydrofuran solution of compound 5, yield：74%.
Using column chromatography purification (developing solvent：Ethyl acetate) obtain compound 5 after purification
Nuclear magnetic data is as follows：1H NMR (400MHz, CDCl3) δ 10.57 (1H, brs), δ 4.54
(1H, dd), 3.95 (1H, dd), 3.30 (1H, d), 2.96-3.03 (1H, m), 1.39-1.76 (2H, m),
1.27-1.35 (2H, m), 0.95 (3H, t).
Embodiment 17 prepare compound 6
The 2- methyltetrahydrofuran solution (1.36 of ethyl grignard reagent is added in reaction bulb
Mol/kg, 64.85g, 88.2mmol), reaction bulb is placed in low-temp reaction bath, controls interior
Temperature is -20--30 DEG C, and CuI (2.24g, 11.79mmol) is being added stirring 0.5 in reaction bulb
Hour, then to the compound 3 that method is obtained as described in Example 1 of Deca in reaction bulb (10.0g,
58.52mmol) 2- methyltetrahydrofuran (10mL) solution is dried.Use 50mL saturation
Ammonium chloride solution is quenched reaction, and after stirring, point liquid, takes organic faciess.Add NaOH/H2O(7g/18
ML), it is stirred at room temperature 2 hours, standing point liquid water intaking phase.Aqueous phase 50mL2- methyl
Oxolane washed once.Add concentrated hydrochloric acid to adjust pH to 1, add 10mL 2- methyl four
Hydrogen furan, point liquid, take organic faciess, aqueous phase is extracted once with 20mL 2- methyltetrahydrofuran.
Merge organic faciess, concentrate and remove solvent.Debris are heated to 105 DEG C and react 10 hours, through subtracting
Pressure is steamed to obtaining compound 6, colourless or weak yellow liquid, yield 75%.
The nuclear magnetic data of compound 6 is as follows：1H NMR (400MHz, CDCl3) δ 4.42 (1H,
Dd), 3.92 (1H, dd), 2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40-1.47 (2H, m),
1.40-1.47 (2H, m), 1.27-1.39 (2H, m), 0.94 (3H, t).
The specific rotatory power of compound 6 is：[α]23 D=+3.9 (C=10, CHCl3)
The application includes but is not limited to above example, carries out under every principle in the application spirit
Any equivalent substitute or local improvement, all will be regarded as within the protection domain of the application.
Claims (19)
1. a kind of method of synthesis Formula VII compound Bu Waxitan
2. the method for claim 1, wherein synthesizes Formula II compound by compound of formula I,
Again formula IV compound is synthesized by Formula II compound design, then Formula V is synthesized by formula IV compound design
Compound, finally synthesizes Formula VII compound Bu Waxitan by Formula V compound design.
3. method as claimed in claim 2, a kind of method for preparing Formula II compound, described
Method includes the step preparing Formula II compound by compound of formula I：
Wherein, R is C1-20Alkyl.Preferably, R be selected from methyl, ethyl, propyl group, pi-allyl,
Normal-butyl, isobutyl group, isopropyl, n-pentyl, n-hexyl, the tert-butyl group or benzyl.Further preferably,
R is selected from methyl, ethyl, the tert-butyl group or benzyl.
4. the method as described in any one of claim 3, wherein said method includes having non-proton
In machine solvent, compound of formula I and ethyl metal reagent is made to react preparation Formula II compound.Wherein said
Ethyl metal reagent includes ethylmagnesium bromide, ethylmagnesium chloride, diethyl zinc, ethyl-lithium or diethyl
One of lead or more kinds of.The use molar equivalent of wherein ethyl metal reagent is between 1-5.Its
Described in ethyl metal reagent be used in combination with Hydro-Giene (Water Science)., Cupricin. or anhydrous zinc chloride.Wherein
The use molar equivalent of described Hydro-Giene (Water Science)., Cupricin. or anhydrous zinc chloride is between 0.01-2.Its
Described in aprotic organic solvent include oxolane, methyltetrahydrofuran, toluene, dichloromethane,
Ether or methyl tertiary butyl ether(MTBE) one or more of.The use molar equivalent of wherein ethyl metal reagent
Between 1-5, the use molar equivalent of Hydro-Giene (Water Science)., Cupricin. or anhydrous zinc chloride is in 0.01-2
Between.
5. method as claimed in claim 2, a kind of method for preparing formula III compound, institute
The method of stating includes the step by Formula II preparation of compounds of formula III compound：
6. method as claimed in claim 5, wherein, in the mixture with water for the organic solvent,
In the presence of alkali or acid, Formula II compound is made to experience hydrolysis to obtain formula III compound.Its
The use molar equivalent of middle alkali or acid is between 0.01-10.Wherein, described alkali include Lithium hydrate,
One of potassium hydroxide or sodium hydroxide or more kinds of, described acid include hydrochloric acid, sulphuric acid, hydrobromic acid,
One of phosphoric acid or more kinds of.Described organic solvent includes oxolane, methyltetrahydrofuran, first
Benzene, dichloromethane, ether and methyl tertiary butyl ether(MTBE) one or more of.Wherein so that Formula II
Compound removes R group by metal catalytic, obtains formula III compound.
7. method as claimed in claim 2, a kind of method for preparing formula IV compound, institute
The method of stating includes the step by formula III preparation of compounds of formula IV compound：
8. method as claimed in claim 7, wherein, under having solvent or condition of no solvent, makes
Formula III compound experience decarboxylic reaction is to obtain formula IV compound.Described solvent include oxolane,
Methyltetrahydrofuran, toluene, dichloromethane, ether and methyl tertiary butyl ether(MTBE), water one or more
Kind.
9. method as claimed in claim 2, a kind of method for preparing Formula II compound, institute
The method of stating includes the step by Formula II preparation of compounds of formula IV compound：
10. method as claimed in claim 9, wherein, in aprotic polar organic solvent and water
Mixture in, in the presence of salt, make Formula II compound experience takes off ester group be reacted to give formula IV
Compound.The use molar equivalent of wherein salt is between 0.01-10.Described salt includes lithium chloride, chlorine
Change sodium, potassium chloride, magnesium chloride or lithium bromide.Described aprotic polar organic solvent includes N- methyl pyrrole
Pyrrolidone, DMF, dimethyl sulfoxide, sulfolane or 4- methyl -2- amylalcohol.
11. methods as claimed in claim 2, a kind of method for preparing Formula V compound, institute
The method of stating includes the step by formula IV preparation of compounds of formula V compound：
12. methods as claimed in claim 11, in the presence of lewis acid and thionyl chloride, make
Formula IV compound experience ring-opening reaction is to obtain Formula V compound.Described lewis acid use mole is worked as
Amount is between 0.01-1.Described lewis acid include zinc dichloride, ferric chloride, ferrous chloride, two
One of copper chloride, aluminum chloride or more kinds of.Described thionyl chloride uses molar equivalent in 1-10
Between.
13. methods as claimed in claim 2, a kind of method for preparing Formula IV compound,
Methods described includes the step by Formula V preparation of compounds of formula VI compound：
14. methods as claimed in claim 13, wherein, in organic solvent, in the effect of alkali
Under, make Formula V compound obtain Formula IV to (S) -2- amino-butanamide or its corresponding salts reaction
Compound.Described alkali uses molar equivalent between 1-5.Described alkali includes triethylamine, diisopropyl second
Base amine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide,
Potassium tert-butoxide, lithium diisopropylamine, two (trimethyl silicon substrate) Lithamide .s or two (trimethyl silicon substrates)
One of Sodamide. or more kinds of.Described organic solvent include oxolane, methyltetrahydrofuran,
Ether, acetone, butanone, dichloromethane, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane, methanol, ethanol,
Isopropanol, DMF, N-Methyl pyrrolidone, dimethyl sulfoxide one or more
Kind.Described (S) -2- amino-butanamide or its corresponding salt use molar equivalent between 0.5-5.
15. methods as claimed in claim 2, one kind is used for preparing Formula VII compound Bu Waxitan
Method, methods described includes the step by Formula IV preparation of compounds of formula VII compound：
16. methods as claimed in claim 15, wherein, in organic solvent, in the effect of alkali
Under, make Formula IV compound occur ring closure reaction to obtain Formula VII compound Bu Waxitan, according to concrete
Situation can add phase transfer catalyst to promote reaction.Described alkali uses molar equivalent between 1-5.Institute
State alkali include triethylamine, diisopropyl ethyl amine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate,
Potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine, two (trimethyl silicanes
Base) one of Lithamide. or two (trimethyl silicon substrate) Sodamide. or more kinds of.Described organic solvent
Including oxolane, methyltetrahydrofuran, ether, acetone, butanone, dichloromethane, chloroform, second
Nitrile, Isosorbide-5-Nitrae-dioxane, methanol, ethanol, isopropanol, DMF, N- methyl pyrrole
Pyrrolidone, dimethyl sulfoxide one or more of.The use molar equivalent of described phase transfer catalyst
Between 0-1.Described phase transfer catalyst includes tetrabutylammonium chloride, tetrabutyl ammonium bromide, four fourths
Base ammonium iodide, one of Polyethylene Glycol or more kinds of.
17. methods as claimed in claim 2, a kind of for preparing Formula V compound Bu Waxitan's
Method, methods described includes the step by Formula V preparation of compounds of formula VII compound：
18. methods as claimed in claim 17, wherein, in organic solvent, in the effect of alkali
Under, make Formula V compound obtain Formula VII to (S) -2- amino-butanamide or its corresponding salts reaction
Compound Bu Waxitan, needs to add phase transfer catalyst to promote reaction as the case may be.Described alkali uses
Molar equivalent is between 1-10.Described alkali includes triethylamine, diisopropyl ethyl amine, pyridine, hydrogen-oxygen
Change sodium, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, two different
In propylcarbamic lithium, two (trimethyl silicon substrate) Lithamide .s or two (trimethyl silicon substrate) Sodamide. one
Plant or more kinds of.Described organic solvent include oxolane, methyltetrahydrofuran, ether, acetone,
Butanone, dichloromethane, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane, methanol, ethanol, isopropanol, N, N-
Dimethylformamide, N-Methyl pyrrolidone, dimethyl sulfoxide one or more of.Described phase turns
The use molar equivalent of shifting catalyst is between 0-1.Described phase transfer catalyst includes tetrabutyl chlorination
Ammonium, tetrabutyl ammonium bromide, tetrabutylammonium iodide, one of Polyethylene Glycol or more kinds of.Described (S)
- 2- amino-butanamide or its corresponding salt use molar equivalent between 0.5-5.
19. methods as described in any one of claim 3-18, methods described comprises the steps：
Wherein, R is C1-20Alkyl.
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| CN201510648574.4A CN106432030B (en) | 2015-10-10 | 2015-10-10 | A kind of preparation method of Bu Waxitan |
| KR1020177037062A KR102630456B1 (en) | 2015-05-25 | 2016-05-24 | Method of manufacturing brivaracetam |
| BR112017025266A BR112017025266A2 (en) | 2015-05-25 | 2016-05-24 | process to produce brivaracetam |
| US15/575,373 US10221134B2 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| JP2017561732A JP6872500B2 (en) | 2015-05-25 | 2016-05-24 | How to make bribalacetam |
| CA2984832A CA2984832A1 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| HUE16800643A HUE064612T2 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| PL16800643.5T PL3302441T3 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| ES16800643T ES2965746T3 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| MX2017015133A MX2017015133A (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam. |
| PCT/US2016/033965 WO2016191435A1 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| HRP20240027TT HRP20240027T1 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| EP16800643.5A EP3302441B1 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| IL255880A IL255880B (en) | 2015-05-25 | 2017-11-23 | Processes to produce brivaracetam |
| US16/256,522 US20240199541A9 (en) | 2015-05-25 | 2019-01-24 | Processes to produce brivaracetam |
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| CN108947883A (en) * | 2017-05-25 | 2018-12-07 | 北京万全德众医药生物技术有限公司 | The preparation of Bu Waxitan |
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| CN108929289A (en) * | 2018-06-19 | 2018-12-04 | 上海博氏医药科技有限公司 | A kind of midbody compound and its preparation method and application being used to prepare Bu Waxitan |
| US11247977B2 (en) | 2018-06-22 | 2022-02-15 | Fujian Haixi Pharmaceuticals Co., Ltd. | Compound and use thereof in synthesis of brivaracetam intermediate and crude drug |
| CN111094260B (en) * | 2018-06-22 | 2021-05-11 | 福建海西新药创制有限公司 | Compound and application thereof in synthesis of Brivaracetam intermediate and bulk drug |
| JP2021528440A (en) * | 2018-06-22 | 2021-10-21 | 福建▲海▼西新▲薬▼▲創▼制有限公司 | Its use in the synthesis of compounds and intermediates and APIs of Brivaracetam |
| CN111094260A (en) * | 2018-06-22 | 2020-05-01 | 福建海西新药创制有限公司 | Compound and application thereof in synthesis of Brivaracetam intermediate and bulk drug |
| JP7117796B2 (en) | 2018-06-22 | 2022-08-15 | 福建▲海▼西新▲薬▼▲創▼制有限公司 | its use in the synthesis of compounds and intermediates and drug substances of Brivaracetam |
| CN108947908B (en) * | 2018-07-11 | 2020-05-19 | 丽珠集团新北江制药股份有限公司 | New intermediate of brivaracetam with imidazole ring and synthesis method and application thereof |
| CN108947908A (en) * | 2018-07-11 | 2018-12-07 | 丽珠集团新北江制药股份有限公司 | The Bu Waxitan new intermediate and its synthetic method of tool imidazole ring and application |
| CN109134406A (en) * | 2018-08-02 | 2019-01-04 | 丽珠集团新北江制药股份有限公司 | A kind of synthetic method of Bu Waxitan intermediate and Bu Waxitan |
| CN112739683A (en) * | 2018-09-12 | 2021-04-30 | 上海宣泰医药科技股份有限公司 | Preparation method and intermediate of brivaracetam |
| CN112739683B (en) * | 2018-09-12 | 2024-04-16 | 上海宣泰医药科技股份有限公司 | Preparation method of brivaracetam and intermediate thereof |
| CN111170881A (en) * | 2018-11-09 | 2020-05-19 | 上海医药集团股份有限公司 | Preparation method of brivaracetam intermediate |
| CN111170881B (en) * | 2018-11-09 | 2023-08-01 | 上海医药集团股份有限公司 | Preparation method of buvaracetam intermediate |
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