CN106432030B - A kind of preparation method of Bu Waxitan - Google Patents
A kind of preparation method of Bu Waxitan Download PDFInfo
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- CN106432030B CN106432030B CN201510648574.4A CN201510648574A CN106432030B CN 106432030 B CN106432030 B CN 106432030B CN 201510648574 A CN201510648574 A CN 201510648574A CN 106432030 B CN106432030 B CN 106432030B
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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
Abstract
The application provides a kind of method for synthesizing Bu Waxitan.The raw material that herein described method is related to is easy to get and cheap, preparation process avoids the appearance for being difficult to isolated chiral isomer, avoid the means of purification that column chromatographic purifying etc. is unfavorable for industry's enlarging production, synthesis process is not related to expensive toxic heavy metal and chiral ligand, the product Bu Waxitan of available high-quality, high-optical-purity.
Description
Technical field
This application involves pharmaceutical synthesis fields, and in particular, to a method of synthesis Bu Waxitan.
Background technique
Epilepsy is the common disease of nervous system, and the disease incidence in crowd is 0.6%~1.1%, wherein 60%~70%
Patient can still break out when taking anti-epilepsy agent, cause a part of patient voluntarily to stop drug therapy.China has about 600 at present
Ten thousand or more epileptic, annual new hair epileptic 650,000~700,000, about 25% is intractable epilepsy.Although current epilepsy
Diagnosis and treatment make great progress, but the quantity for the treatment of of intractable epilepsy is increasing.Broad sense intractable epilepsy refers to
Using current antiepileptic (AEDs) Canonical management, cannot terminate its breaking-out or by clinical confirmation be refractory epilepsy and
Epilepsy syndromes.
Bu Waxitan (Brivaracetam) is the synaptic vesicle proteins 2A ligand of a novel high-affinity, be can inhibit
Neuronal voltagedependent sodium channel, for treating intractable epilepsy partial seizures.The II phase of Bu Waxitan, III phase are clinical
Test all has a better effect.The incidence of the main adverse events of Bu Waxitan is similar to the incidence of placebo, is
Slightly to the fatigue of moderate, headache, nasopharyngitis, nausea, drowsiness and dizzy.No patient interrupts treatment because of adverse events.As a result
Show Bu Waxitan piece to be in 16~65 years old intractable epilepsy partial seizures patient be the adjuvant treatment age it is effective and
Tolerance is good.In general, it is insane to be that the very good third generation of a prospect after Levetiracetam resists by Bu Waxitan
Epilepsy class drug.
So far, the domestic patent about Bu Waxitan synthesis has not been reported.External related patents report is also few,
Such as patent US 6,784,197, US 7,629,474, US 8,957,226, US 8,338,621, US 8,076,493 and its
Related patents report the synthesis of Bu Waxitan, wherein 6 US, and 784,197, US 7,629,474 report synthesis road below
Line:
US 8,957,226 (embodiment 1,3) and US 8,338,621 (embodiment 4,11) report synthesis road below
Line:
Kenda etc. (Joumal of Medicinal Chemistry, 2004,47,530) reports following synthetic route:
Above-mentioned several routes had not all constructed the chiral centre of n-propyl on butyrolactam, but passed through in final product
The method of Chiral HPLC purifying obtains the Bu Waxitan of optical purity, and the utilization of raw material is simultaneously uneconomical.
Accordingly, there exist the demands to the simple and cost-effective method for preparing Bu Waxitan, to obtain high-optical-purity
Bu Waxitan.
Summary of the invention
The purpose of the application is to provide a kind of method for synthesizing Formula VII Bu Waxitan, and defect, provides in view of the prior art
A kind of at low cost, yield is good, the new method of the Bu Waxitan of the strong suitable industrialized production of controllability.
The application provides a kind of method for synthesizing Formula VII Bu Waxitan, and described method includes following steps:
Wherein, R C1-20Alkyl, it is preferable that R is methyl, ethyl, propyl, allyl, normal-butyl, isobutyl group, isopropyl
Base, n-pentyl, n-hexyl, tert-butyl or benzyl, more preferably R are ethyl.
In some embodiments, R can be methyl, ethyl, propyl, allyl, normal-butyl, isobutyl group, isopropyl
Base, n-pentyl, n-hexyl, tert-butyl or benzyl.
Those skilled in the art will be further understood that according to above-described synthetic route, those skilled in the art
Be fully able to according to its common technical knowledge and conventional technical means, by reasonably select raw material known in the art and synthetic method come
Product required for obtaining.
In a specific embodiment, the reaction condition of each reaction step may is that
By compound of formula I preparation formula II compound:
- 78 DEG C to 200 DEG C at a temperature of, in aprotic organic solvent, keep compound of formula I and ethyl metal reagent anti-
Preparation formula II compound is answered, wherein the use molar equivalent of ethyl metal reagent can be between 1-5；Preferably, the ethyl
Metal reagent can be selected from one of ethylmagnesium bromide, ethylmagnesium chloride, diethyl zinc, ethyl-lithium and lead diethide or more
Kind；It is highly preferred that the ethyl metal reagent can be used in combination with cuprous iodide, cuprous cyanide or anhydrous zinc chloride, reaction
The use molar equivalent of middle cuprous iodide, cuprous cyanide or anhydrous zinc chloride is between 0.01-2；Preferably, described non-proton to have
Solvent can be in tetrahydrofuran (THF), methyltetrahydrofuran, toluene, methylene chloride, ether and methyl tertiary butyl ether(MTBE)
It is one or more of；
By Formula II preparation of compounds of formula III compound:
In the mixture of organic solvent and water, in the presence of alkali, make Formula II within the temperature range of 0 DEG C -200 DEG C
Object experience hydrolysis is closed to obtain formula III compound, wherein the use molar equivalent of alkali is between 0.01-10；Preferably, institute
It states alkali and is selected from one of lithium hydroxide, potassium hydroxide or sodium hydroxide or more, the organic solvent can be selected from tetrahydro
One of furans, methyltetrahydrofuran, toluene, methylene chloride, ether and methyl tertiary butyl ether(MTBE) or more；
Or, Formula II compound can be made to remove R group by metal catalytic if R contains unsaturated part.
By formula III preparation of compounds of formula IV compound:
In solvent-free or organic solvent, in a heated condition, make formula III chemical combination within the temperature range of 50 DEG C -200 DEG C
Object undergoes decarboxylic reaction to obtain formula IV compound；Preferably, the organic solvent can be selected from tetrahydrofuran, methyl tetrahydro furan
It mutters, one of toluene, methylene chloride, ether and methyl tertiary butyl ether(MTBE) or more；
Formula II compound obtains formula III compound via hydrolysis, then decarboxylation is closed compound of formula IV and can effectively be mentioned
The yield and purity of high product, and the complexity operated does not obviously increase.
By Formula II preparation of compounds of formula IV compound:
In the mixture of aprotic polar organic solvent and water, under the action of salt or alkali, in 50 DEG C -200 DEG C of temperature
Make the experience takes off ester group reaction of Formula II compound to obtain formula IV compound in degree range, wherein the use molar equivalent of salt or alkali exists
Between 0.01-10；Preferably, the salt is selected from one of lithium chloride, sodium chloride, potassium chloride, magnesium chloride and lithium bromide or more
A variety of, the alkali is selected from one of lithium hydroxide, potassium hydroxide or sodium hydroxide or more, and the aprotonic polar is organic
Solvent is in N-Methyl pyrrolidone, n,N-Dimethylformamide, dimethyl sulfoxide, sulfolane and 4- methyl -2- amylalcohol
It is one or more of；
Formula IV compound can be used as reactant and solvent under conditions of high temperature and pressure with (S) -2- amino-butanamide or
Its corresponding salt, or directly reacted to (S) -2- amino n-butyl alcohol and obtain the corresponding Bu Waxitan synthesized or its key intermediate.
By formula IV preparation of compounds of formula V compound:
Wherein 0 DEG C to reflux at a temperature of, it is preferable that at a temperature of between 55 DEG C -80 DEG C, in ZnCl2Effect
Under, react thionyl chloride with formula IV compound: preferably, thionyl chloride is simultaneously as the solvent of reaction and making for thionyl chloride
With molar equivalent between 1-50, it is highly preferred that the thionyl chloride uses molar equivalent between 1-5.
By reacting come the compound of preparation formula VI for Formula V compound and (S) -2- amino butanamide or its salt:
Wherein under alkaline condition, in organic solvent, -50 DEG C -50 DEG C at a temperature of, make Formula V compound and (S) -
2- amino butanamide or its reactant salt carry out preparation formula VI compound, wherein the use mole for being used to form the alkali of alkaline condition is worked as
Amount is between 1-5, and the use molar equivalent of (S) -2- amino-butanamide or its salt is between 0.5-5；Preferably, the alkali is selected from
Triethylamine, diisopropyl ethyl amine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, uncle
One of butanol potassium, lithium diisopropylamine, two (trimethyl silicon substrate) lithium amides or two (trimethyl silicon substrate) Sodamides or more
It is a variety of, the organic solvent be selected from tetrahydrofuran, methyltetrahydrofuran, ether, acetone, butanone, methylene chloride, chloroform, acetonitrile,
Isosorbide-5-Nitrae-dioxane, methanol, ethyl alcohol, isopropanol, n,N-Dimethylformamide, N-Methyl pyrrolidone, in dimethyl sulfoxide
It is one or more of.Preferably, using inorganic weak bases such as potassium carbonate, acetone, acetonitrile, n,N-Dimethylformamide etc. it is water-soluble compared with
Good solvent is as reaction dissolvent；Alkali used in improving and reaction medium, effectively inhibit disappearing for (S) -2- amino group
Rotation.Post-processing operation is simplified as reaction medium using water-miscible organic solvent, post-processing purifying can effectively improve production
The optical purity of object, and to obtain the Formula IV compound of high-purity in high yield.
The method that Bu Waxitan is prepared by Formula IV compound:
Wherein under alkaline condition, in organic solvent, -78 DEG C -100 DEG C at a temperature of, make Formula IV occur itself close
Ring reacts preparation formula VII Bu Waxitan, wherein being used to form the use molar equivalent of the alkali of alkaline condition between 1-5；It is preferred that
Ground, the alkali are selected from triethylamine, diisopropyl ethyl amine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, hydrogenation
Sodium, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine, two (trimethyl silicon substrate) lithium amides or two (trimethyl silicon substrate) amino
One of sodium or more, organic solvent be selected from tetrahydrofuran, methyltetrahydrofuran, ether, acetone, butanone, methylene chloride,
Chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane, methanol, ethyl alcohol, isopropanol, n,N-Dimethylformamide, N-Methyl pyrrolidone, diformazan
One of base sulfoxide or more.Preferably, using inorganic bases such as potassium hydroxide, N-Methyl pyrrolidone, dimethyl sulfoxide,
The aprotic polar solvents such as n,N-Dimethylformamide are as reaction dissolvent；Alkali used in improving and reaction medium, effectively
The racemization for inhibiting (S) -2- amino group, and to obtain the Formula VII compound Bu Waxitan of high-purity in high yield.
The method for preparing Bu Waxitan is reacted by Formula V compound and (S) -2- amino butanamide or its salt:
Wherein under alkaline condition, in organic solvent, -50 DEG C -50 DEG C at a temperature of, make Formula V compound and (S) -
2- amino butanamide or its reactant salt carry out preparation formula VII compound Bu Waxitan, wherein being used to form making for the alkali of alkaline condition
With molar equivalent between 1-10, the use molar equivalent of (S) -2- amino-butanamide or its salt is between 0.5-5；Preferably,
The alkali is 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) lithium amides or two (trimethyl silicon substrate) Sodamides or more, the organic solvent
Selected from tetrahydrofuran, methyltetrahydrofuran, ether, acetone, butanone, methylene chloride, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane, first
One of alcohol, ethyl alcohol, isopropanol, n,N-Dimethylformamide, N-Methyl pyrrolidone, dimethyl sulfoxide or more.?
It is necessary in the case where, need to add the progress that phase transfer catalyst promotes reaction, wherein the use equivalent of phase transfer catalyst
In 0-1.Between；Preferably, the phase transfer catalyst be selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide,
One of polyethylene glycol or more.Preferably, using the inorganic bases such as potassium hydroxide, methylene chloride, acetonitrile, acetone equal solvent
As reaction dissolvent；Polyethylene glycol 400 improves used alkali, phase transfer catalyst and reaction as phase transfer catalyst
Medium effectively inhibits the racemization of (S) -2- amino group, and a step is efficient, obtains the Formula VII compound of high-purity in high yield
Bu Waxitan.
In a specific exemplary embodiment, the method may include following steps:
Wherein, R C1-20Alkyl, it is preferable that R is ethyl.
In above or other embodiments, compound of formula I can be commercial products, such as super happy chemical article No. SP-
13711 product.
In above or other embodiments, compound of formula I can also be prepared in the following manner:
Wherein, R C1-20Alkyl, wherein reaction temperature is 0 DEG C -100 DEG C, and alkali uses molar equivalent between 1 and 3, is changed
That closes object IX uses molar equivalent between 0.5-3；Preferably, the alkali is selected from one of metallic sodium, metallic potassium or more
Kind, it is highly preferred that the metallic sodium is sodium methoxide, sodium ethoxide or sodium tert-butoxide, the metallic potassium is potassium tert-butoxide；It is described organic
Solvent is selected from one of ethyl alcohol, methanol, propyl alcohol, isopropanol or more.
Compared with prior art, the method for synthesizing Bu Waxitan of the application has the advantage that
1, raw material is easy to get and cheap.
2, intermediate and product isolate and purify it is easy, in this embodiment it is not even necessary to purify, can directly do in next step tandem reaction
Bu Waxitan and its similar compound are prepared, it is easy to operate.
3, due to constructing the chiral centre of the n-propyl on butyrolactam at the very start, available high-optical-purity
Bu Waxitan, without expensive toxic heavy metal and chiral ligand.
4, it Bu Waxitan is prepared by method described herein avoids and be difficult to the appearance of isolated chiral isomer, keep away
Exempted from the means of purification that column chromatographic purifying etc. is unfavorable for industry's enlarging production, synthesis process be not related to expensive toxic heavy metal and
Chiral ligand obtains high-quality, (in four kinds of optical isomers, Bu Waxitan ratio is greater than the product of high-optical-purity
99.5%), remaining single contaminant efficient liquid phase peak area is split less than 0.1% without using expensive Chiral HPLC method,
Avoid waste of the chiral resolution for raw material.The gross production rate about 50% that Bu Waxitan is prepared by compound of formula I, tears open higher than existing
Shunt lead.
Specific embodiment
Presently filed embodiment is described below by embodiment, it will be appreciated by the person skilled in the art that these
Specific embodiment only indicates to achieve the purpose that the application and the implementation technical solution that selects, is not to technical solution
Limitation.According to teachings of the present application, be to the improvement of technical scheme in conjunction with the prior art it is obvious, belong to the application
The range of protection.
Implementation condition used in the examples can do further adjustment according to specific requirement, and the implementation condition being not specified is logical
It is often the condition in routine experiment.
Wherein, the chemical reagent used in the examples below is commercially available chemical reagent.
In an exemplary embodiment of the present invention embodiment, Bu Waxitan is synthesized using following route:
In said synthesis route, those skilled in the art can also make a change said synthesis route, such as basis
It needs to change specific reaction condition or the synthetic route of a certain step or a few steps is adjusted, these are without departing from of the invention
Substantive content change made is within the scope of protection of this application.
1 prepare compound 3 of embodiment
It is complete that dissolution in 44.5kg dehydrated alcohol is added in sodium methoxide (2.0kg, 37.03mol), if being added at outer 10 DEG C of temperature
Diethyl malonate (6.0kg, 37.46mol).It stirs 10 minutes at this temperature, system is warmed to room temperature, and is delayed into reaction system
It is slow that (R)-epoxychloropropane (ee > 99%) (3.3kg, 35.67mol) (purchased from resistance to Jilin Chemical is pacified) is added, it finishes, system reflux
Under the conditions of react 2 hours, stop reaction, system is cooled to room temperature, and is spin-dried for solvent, 19.03kg water is added, with 17.0kg and 12kg
Ethyl acetate extracts 2 times.Merge organic phase, anhydrous sodium sulfate is dry, and drying finishes, and filters, filtrate is spin-dried for, through being evaporated under reduced pressure to
Colourless liquid obtains compound 3, yield 50%.3 chirality HPLC (ee 98.5%) of compound
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).
2 prepare compound 4 of embodiment
Into reaction kettle be added ethyl grignard reagent 2- methyltetrahydrofuran solution (1.29mol/kg, 2.44kg,
3.14mol), temperature is -20--30 DEG C in control, and CuI (108.3g, 0.57mol) is added in reaction system, stirs 30min, then
The drying 2- methyl tetrahydro furan of compound 3 (434g, 2.55mol) made from method as described in Example 1 is added dropwise into reaction flask
It mutters solution.It is added dropwise, after stirring 30 minutes at this temperature, with saturated ammonium chloride quenching reaction, liquid separation obtains the 2- of compound 4
Methyltetrahydrofuran solution, yield: 64%.
Compound 4 after purification is obtained using column chromatographic purifying (solvent polarity: petrol ether/ethyl acetate=10/1)
Nuclear magnetic data is as follows:1H NMR (400MHz, CDCl3) δ 4.52 (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).
Compound 4 after purification is obtained using column chromatographic purifying (solvent polarity: petrol ether/ethyl acetate=10/1)
Specific rotatory power are as follows: [α]23 D=+22.6 (C=10, CHCl3)
3 prepare compound 4 of embodiment
Into reaction flask be added ethyl grignard reagent 2- methyltetrahydrofuran solution (1.29kg/mol, 63.51g,
81.93mmol), reaction flask is placed in low-temp reaction bath, controlling interior temperature is -20--30 DEG C, by CuI (2.22g, 11.70mol)
It is stirred 0.5 hour in reaction flask is added, then compound 3 made from method as described in Example 1 is added dropwise into reaction flask
The drying 2- methyltetrahydrofuran solution of (10.0g, 58.52mmol).It is added dropwise, after stirring 30 minutes at this temperature, uses
Saturated ammonium chloride quenching reaction, liquid separation obtain the 2- methyltetrahydrofuran solution of compound 4, yield: 87%.
Compound 4 after purification is obtained using column chromatographic purifying (solvent polarity: petrol ether/ethyl acetate=10/1)
Nuclear magnetic data is as follows:1H NMR (400MHz, CDCl3) δ 4.52 (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).
Compound 4 after purification is obtained using column chromatographic purifying (solvent polarity: petrol ether/ethyl acetate=10/1)
Specific rotatory power are as follows: [α]23 D=+22.6 (C=10, CHCl3)
4 prepare compound 5 of embodiment
By the 2- methyltetrahydrofuran solution of compound 4 made from method as described in Example 3, NaOH/H is added2O
(255g/640mL), system react liquid separation after 2h at room temperature, obtain water phase and are washed once with 1L ethyl acetate, and enriching hydrochloric acid tune pH is
1, add 1L 2- methyltetrahydrofuran to be extracted twice, merge organic phase, concentration obtains compound 5, yield after steaming using toluene set
99%
The nuclear magnetic data for obtaining compound 5 after purification using column chromatographic purifying (solvent: ethyl acetate) 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).
5 prepare compound 6 of embodiment
Compound 5 made from method as described in Example 4 is added in reaction flask, if outer 120 DEG C of temperature, is down to after reacting 2h
Room temperature is evaporated under reduced pressure to 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 are as follows: [α]23 D=+3.9 (C=10, CHCl3)
6 prepare compound 6 of embodiment
Compound 5 made from method as described in Example 4 is added in reaction flask, 2vol toluene is added, if outer temperature 120
DEG C, it is down to room temperature after reacting 8h, is evaporated under reduced pressure to compound 6, yield: 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 are as follows: [α]23 D=+3.9 (C=10, CHCl3)
7 prepare compound 7 of embodiment
Anhydrous zinc chloride (10.6g, 0.078mol) is added in the reaction flask for having compound 6 (100g, 0.78mol), then
Reaction will be added in 200mL thionyl chloride.Reaction flask is placed in 85 DEG C of oil baths and is reacted, to GC detection without starting material left, is stopped
Reaction, system are cooled to room temperature, and screw out thionyl chloride, then obtain the compound 7 of yellowish liquid, yield through vacuum distillation
79.7%.
The nuclear magnetic data of compound 7 is as follows:1H NMR (400MHz, CDCl3):1HNMR (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 are as follows: [α]23 D=+2.9 (C=10, CHCl3)
8 prepare compound 8 of embodiment
(S) -2- amino-butanamide hydrochloride (10g, 72.5mmol) (being coupled Science and Technology Ltd. purchased from Beijing) is added
In the dry acetonitrile of 150mL, it is added potassium carbonate (25g, 181.3mmol), after stirring 30 minutes at 0 DEG C, compound 7 is added dropwise
(14.6g, 79.71mmol), is added dropwise, and is stirred at room temperature to TLC and detects without starting material left.It is spin-dried for, 150mL dichloromethane is added
Alkane, 150mL water, 10mL ethyl alcohol, extraction separate organic phase, and primary, merging organic phase, anhydrous sulphur are extracted with 100mL methylene chloride
Sour sodium is dry, and drying finishes, and filters, and filtrate is concentrated to get compound 8, yield 96%.
It is further purified to obtain the compound 8 of high-purity using recrystallization.The nuclear magnetic data of compound 8 after purification is such as
Under: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 are as follows: [α]25 D=-23.7 (C=3, CH3OH)
Embodiment 9 prepares Bu Waxitan compound 9
It is added in dry DMF 6mL, compound 8 (2.0g, 8mmol) made from method as described in Example 8 by hydrogen-oxygen
Change potassium (670mg, 12mmol) to be added in reaction flask in five times.System is surplus without raw material to HPLC detection in -15 to -10 DEG C of reactions
Remaining, 12vol saturated salt solution is added in the reaction of 1N hydrochloric acid, and methyl tertiary butyl ether(MTBE) extracts four times, merges organic phase, saturation
NaCl solution washed once, and anhydrous sodium sulfate dries, filters, and filtrate is concentrated to give product, and obtained solid is Bu Waxitan, yield
95%, high-purity product, the product of chiral HPLC > 99.5% can be obtained through further recrystallization purifying.
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
(S) -2- amino-butanamide hydrochloride (8.0g, 58mmol) (being coupled Science and Technology Ltd. purchased from Beijing) is added
In 120mL dry methylene chloride, it is added PEG400 (3.5g, 8.7mmol), is down at -10 DEG C after stirring 30 minutes, is added portionwise
Compound 7 (11.7g, 64mmol) is added dropwise therebetween, is added dropwise by KOH (17.9g, 320mmol), and -2 DEG C of stirrings to TLC are examined
It surveys without starting material left.Semi-saturation ammonium chloride quenching reaction, extraction separate organic phase, are extracted twice with 40mL methylene chloride, merge
Organic phase, anhydrous sodium sulfate dry, filter, and filtrate is concentrated to give product, and products therefrom is Bu Waxitan, yield 92%, through into
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
(S) -2- amino-butanamide hydrochloride (2.5g, 18mmol) (being coupled Science and Technology Ltd. purchased from Beijing) is added
In 40mL dry methylene chloride, it is added tetrabutylammonium bromide (1.16g, 3.6mmol), is down at -10 DEG C after stirring 30 minutes, point
It criticizes and KOH (4.53g, 81mmol) is added, compound 7 (3.66g, 20mmol) is added dropwise therebetween, is added dropwise, -2 DEG C of stirrings are extremely
TLC is detected without starting material left.Semi-saturation ammonium chloride quenching reaction, extraction separate organic phase, are extracted twice with 40mL methylene chloride,
Merging organic phase, anhydrous sodium sulfate dries, filters, and filtrate is concentrated to give product, and products therefrom is Bu Waxitan, yield 83%,
High-purity product, the product of chiral HPLC > 99% can be obtained through further recrystallization purifying.
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
Compound 8 (2.5g, 10mmol) made from method as described in Example 8 is added in dry methylene chloride 20mL,
Tetrabutylammonium bromide (161mg, 0.5mmol) is added potassium hydroxide (730mg, 13mmol) is added in two portions in reaction flask.Body
It ties up to -15 to -10 DEG C of reactions to detect to HPLC without starting material left, saturated ammonium chloride quenching reaction, methylene chloride extracts three times, closes
And organic phase, anhydrous sodium sulfate dry, filter, filtrate is concentrated to give product, and products therefrom is Bu Waxitan, yield 68%, warp
Further recrystallization purifying can obtain high-purity product, 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
By compound 8 (100mg, 0.4mmol) made from method as described in Example 8, dry methylene chloride 1mL is added
In, PEG400 (24mg, 0.06mmol) is added, sodium hydroxide (32mg, 0.8mmol) is added in reaction flask.System -15 to -
10 DEG C of reactions are detected to HPLC without starting material left, saturated ammonium chloride quenching reaction, and methylene chloride extracts three times, merge organic phase,
Anhydrous sodium sulfate dries, filters, and filtrate is concentrated to give product, and products therefrom is Bu Waxitan, 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
By compound 8 (100mg, 0.4mmol) made from method as described in Example 8, it is added in dry acetonitrile 1mL, adds
Enter PEG400 (24mg, 0.06mmol) potassium hydroxide (45mg, 0.8mmol) is added in reaction flask.System is at -15 to -10 DEG C
Reaction is detected to HPLC without starting material left, and saturated ammonium chloride quenching reaction is spin-dried for organic solvent, is extracted with dichloromethane three times,
Merge organic phase, anhydrous sodium sulfate dries, filters, and filtrate is concentrated to give product, and products therefrom is 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
By compound 8 (100mg, 0.4mmol) made from method as described in Example 8, it is added in dry acetone 1mL, adds
Enter PEG400 (24mg, 0.06mmol) potassium hydroxide (45mg, 0.8mmol) is added in reaction flask.System is at -15 to -10 DEG C
Reaction is detected to HPLC without starting material left, and saturated ammonium chloride quenching reaction is spin-dried for organic solvent, is extracted with dichloromethane three times,
Merge organic phase, anhydrous sodium sulfate dries, filters, and filtrate is concentrated to give product, and products therefrom is 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).
15 prepare compound 6 of embodiment
CuI (9.5g, 50mol) is added in 100mL dry THF, reaction flask is placed in -30 DEG C of low-temp reaction baths, to
The THF solution (1.0M, 300mL, 300mmol) that ethyl grignard reagent is added in reaction flask stirs 1 hour, then drips into reaction flask
Add the dry THF solution of compound 3 (20g, 117mmol) made from method as described in Example 1.It is added dropwise, in this temperature
After lower stirring 30 minutes, it is to slowly warm up to -15 DEG C.With saturated ammonium chloride quenching reaction, 1L water is added, is extracted with 1L ethyl acetate
Three times, merge organic phase, anhydrous sodium sulfate is dry, and drying finishes, and filters, and filtrate is concentrated to get compound 4.By this compound 4
DMSO/H is added2LiCl (14.7g, 350mmol) is added in reaction flask O (400mL/20mL).System is in 140 DEG C of reaction 18h
Later, it is poured into 400mL water, three times with the extraction of 400mL ethyl acetate, merges organic phase, saturation NaCl solution washed once, nothing
Aqueous sodium persulfate dries, filters, and 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 are as follows: [α]23 D=+3.9 (C=10, CHCl3)
16 prepare compound 5 of embodiment
Into reaction flask be added ethyl grignard reagent 2- methyltetrahydrofuran solution (1.36mol/kg, 64.85g,
88.2mmol), reaction flask is placed in low-temp reaction bath, controlling interior temperature is -20--30 DEG C, by CuI (2.24g, 11.79mmol)
It is stirred 0.5 hour in reaction flask is added, then compound 3 made from method as described in Example 1 is added dropwise into reaction flask
Drying 2- methyltetrahydrofuran (10mL) solution of (10.0g, 58.52mmol).60mL 3NHCl aqueous solution quenching reaction is added.
After the mixed liquor is heated to reflux 24 hours, liquid separation is stood, obtains the 2- methyltetrahydrofuran solution of compound 5, yield:
74%.
The nuclear magnetic data for obtaining compound 5 after purification using column chromatographic purifying (solvent: ethyl acetate) 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).
17 prepare compound 6 of embodiment
Into reaction flask be added ethyl grignard reagent 2- methyltetrahydrofuran solution (1.36mol/kg, 64.85g,
88.2mmol), reaction flask is placed in low-temp reaction bath, controlling interior temperature is -20--30 DEG C, by CuI (2.24g, 11.79mmol)
It is stirred 0.5 hour in reaction flask is added, then compound 3 made from method as described in Example 1 is added dropwise into reaction flask
Drying 2- methyltetrahydrofuran (10mL) solution of (10.0g, 58.52mmol).With 50mL saturated ammonium chloride solution quenching reaction,
Liquid separation after stirring, takes organic phase.NaOH/H is added2O (7g/18mL) is stirred at room temperature 2 hours, stands liquid separation water intaking phase.Water
Mutually it washed once with 50mL2- methyltetrahydrofuran.Concentrated hydrochloric acid is added and adjusts pH to 1,10mL 2- methyltetrahydrofuran is added, point
Liquid, takes organic phase, and water phase 20mL 2- methyltetrahydrofuran extracts primary.Merge organic phase, concentration removes solvent.Liquid Residue
It is heated to 105 DEG C to react 10 hours, steam through decompression 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 are as follows: [α]23 D=+3.9 (C=10, CHCl3)
The application includes but is not limited to above embodiments, it is all carried out under the principle of the application spirit any equally replace
Generation or local improvement, all will be regarded as within the scope of protection of this application.
Claims (6)
1. a kind of method for being used to prepare Formula VII compound Bu Waxitan, the method includes passing through Formula V down in the presence of alkali
Compound and (S) -2- amino-butanamide or its corresponding salt, obtain Formula VII compound cloth through single step reaction in organic solvent
Wa Xitan:
2. the method for claim 1, wherein the alkali uses molar equivalent between 1-10 compared to compound V.
3. method as described in claim 1, wherein the alkali includes sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide, uncle
One of butanol potassium, lithium diisopropylamine, two (trimethyl silicon substrate) lithium amides or two (trimethyl silicon substrate) Sodamides or more
It is a variety of.
4. the method for claim 1, wherein the organic solvent include tetrahydrofuran, methyltetrahydrofuran, ether,
Acetone, butanone, methylene chloride, chloroform, acetonitrile, 1,4- dioxane, methanol, ethyl alcohol, isopropanol, N,N-dimethylformamide,
The one or more of N-Methyl pyrrolidone, dimethyl sulfoxide.
5. the progress that phase transfer catalyst promotes reaction the method for claim 1, wherein can be added, the phase turns
Shifting catalyst uses molar equivalent between 0-1 compared to compound V's, and the phase transfer catalyst includes tetrabutyl chlorination
Ammonium, tetrabutylammonium bromide, tetrabutylammonium iodide, one of polyethylene glycol or more.
6. the method for claim 1, wherein (the S) -2- amino-butanamide or its corresponding salt are compared to compound
V's uses molar equivalent between 0.5-5.
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| HRP20240027TT HRP20240027T1 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| CA2984832A CA2984832A1 (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 |
| EP16800643.5A EP3302441B1 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
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| MX2017015133A MX2017015133A (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam. |
| ES16800643T ES2965746T3 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| US15/575,373 US10221134B2 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| 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 |
| IL255880A IL255880B (en) | 2015-05-25 | 2017-11-23 | Processes to produce brivaracetam |
| US16/256,596 US11673862B2 (en) | 2015-05-25 | 2019-01-24 | Processes to produce brivaracetam |
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| CN110606817B (en) * | 2018-06-14 | 2023-01-24 | 广东东阳光药业有限公司 | Refining method of brivaracetam |
| CN108929289B (en) * | 2018-06-19 | 2022-01-04 | 上海博氏医药科技有限公司 | Intermediate compound for preparing brivaracetam and preparation method and application thereof |
| EP3798211A4 (en) * | 2018-06-22 | 2021-09-15 | Fujian Haixi Pharmaceuticals Co., Ltd | Compound and use thereof in synthesis of brivaracetam intermediate and crude drug |
| 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 |
| 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 |
| WO2020051796A1 (en) * | 2018-09-12 | 2020-03-19 | 上海宣泰医药科技有限公司 | Preparation method for brivaracetam and intermediate thereof |
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