CN106365986A - Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam - Google Patents
Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam Download PDFInfo
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- JIHMIJKVXCTYOW-UHFFFAOYSA-N CCCC(C)CC(NC(C)(CC)SC(N)=O)O Chemical compound CCCC(C)CC(NC(C)(CC)SC(N)=O)O JIHMIJKVXCTYOW-UHFFFAOYSA-N 0.000 description 1
- JNQKFQHITVBHPL-ULUSZKPHSA-N CCC[C@H](CC(N)O)CN Chemical compound CCC[C@H](CC(N)O)CN JNQKFQHITVBHPL-ULUSZKPHSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/38—Acyl halides
- C07C53/46—Acyl halides containing halogen outside the carbonyl halide group
- C07C53/50—Acyl halides containing halogen outside the carbonyl halide group of acids containing three or more carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
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- 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
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings 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
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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Abstract
The present invention provides compounds represented by formulas II and IV. The invention further provides uses of the compound represented by the formula II in synthesis of brivaracetam, and a synthesis method. According to the present invention, the used raw materials are easy to obtain and have low price, and the high optical-purity brivaracetam can be prepared. The formulas II and IV are defined in the specification.
Description
Technical field
The application is related to pharmaceutical synthesis field, in particular it relates to compound and preparation method thereof and its
Purposes in synthesis Bu Waxitan.The application further 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 some synthetic routes, the problems of these synthetic routes
It is concentrated mainly on it is impossible to the enough Bu Waxitan of the synthesizing optical purity of enough high yields, high selectivity,
There is the behaviour needing column chromatography purification, chiral high performance liquid chromatography purification etc. to be unfavorable for industry's enlarging production
Make method.
Accordingly, there exist to simple and with low cost, without chiral separation, be easy to industry amplification preparation
The demand of the method for Bu Waxitan, to obtain the Bu Waxitan of high-purity, high optical activity.
Content of the invention
The purpose of the application is to provide a kind of formula ii compound and preparation method thereof.
The further object of the application is that offer formula ii compound is used for synthesis with the use of formula v Bu Waxitan
On the way.
The other purpose of the application is to provide a kind of formula iv compound and preparation method thereof.
A further object of the application is to provide a kind of method of synthesis type v Bu Waxitan.
On the one hand, the application provides a kind of compound, and described compound has a structure of formula ii:
On the other hand, the application provides a kind of method for formula ii compound, methods described bag
Include the step by formula i preparation of compounds of formula ii compound:
It will be appreciated by those skilled in the art that can be by open-loop method known in the art by formula
I preparation of compounds of formula ii compound, such as by making formula i compound in zncl2In the presence of with two
The reaction of chlorine sulfoxide obtains formula ii compound.
In above or other embodiment, can arrive at a temperature of backflow at 0 DEG C it is preferable that
At a temperature of between 55 DEG C -80 DEG C, in zncl2In the presence of, make thionyl chloride anti-with formula i compound
Should；Preferably, simultaneously as the solvent of reaction and the use molar equivalent of thionyl chloride exists thionyl chloride
Between 1-50, it is highly preferred that the use molar equivalent of described thionyl chloride is between 2-5.
In some embodiments, can be by following formula i compound:
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 above or other embodiment, formula vi compound can be commercial products, such as super happy
The product of chemical article No. sp-13711.
In above or other embodiment, formula vi compound also can be prepared in the following manner:
Wherein reaction temperature be 0 DEG C -100 DEG C, the use molar equivalent of alkali between 1 and 3, compound 2
Use molar equivalent between 1 and 3；Preferably, described alkali be selected from metallic sodium, in metallic potassium one
Plant or more kinds of, it is highly preferred that described metallic sodium is Feldalat NM, Sodium ethylate or sodium tert-butoxide, described
Metallic potassium is potassium tert-butoxide；Described organic solvent 4 is in ethanol, methanol, propanol, isopropanol
One or more of.
In above or other embodiment, wherein:
By formula vi preparation of compounds of formula vii compound:
At a temperature of -78 DEG C to 200 DEG C, in aprotic organic solvent, make formula vi compound with
Ethyl metal reagent reacts formula vii compound, the wherein use molar equivalent of ethyl metal reagent
Between 1-5；Preferably, described ethyl metal reagent be selected from ethylmagnesium bromide, ethylmagnesium chloride,
One of diethyl zinc, ethyl-lithium and lead diethide or more kinds of；It is highly preferred that described ethyl gold
Belong to reagent to be used in combination with Hydro-Giene (Water Science)., Cupricin. or anhydrous zinc chloride, Hydro-Giene (Water Science). in reaction,
The use molar equivalent of Cupricin. or anhydrous zinc chloride is between 0.01-2；Preferably, described non-matter
Sub- organic solvent is selected from oxolane (thf), methyltetrahydrofuran, toluene, dichloromethane, ether
With one of methyl tertiary butyl ether(MTBE) or more kinds of；
By formula vii preparation of compounds of formula i compound:
In the mixture with water for the water miscible high boiling organic solvent, in the presence of salt or alkali,
Formula vii compound experience takes off ester group is made to be reacted to give formula i chemical combination within the temperature range of 50 DEG C -200 DEG C
The use molar equivalent of thing, wherein salt or alkali is between 0.01-10；Preferably, described salt is selected from chlorine
Change one of lithium, sodium chloride, potassium chloride, magnesium chloride and lithium bromide or more kinds of, described alkali is selected from
One of Lithium hydrate, potassium hydroxide or sodium hydroxide or more kinds of, described water miscible high boiling point
Organic solvent is selected from n- methyl pyrrolidone, n, n- dimethylformamide, dimethyl sulfoxide, sulfolane
With one of 4- methyl -2- amylalcohol or more kinds of；
If or, r contains unsaturated part, formula vii compound is made to first pass through metal catalytic removing
R group, then obtains formula i compound through decarboxylic reaction within the temperature range of 25 DEG C -200 DEG C；Excellent
Selection of land, described deacidification reaction is selected from toluene, methyl tertiary butyl ether(MTBE), n- methyl pyrrolidone, n, n-
Carry out in one or more of dimethylformamide and dimethyl sulfoxide.
It yet still another aspect, the application provides a kind of compound, described compound has a structure of formula iv:
It yet still another aspect, the application provides a kind of method for preparing above-mentioned formula iv compound, institute
The method of stating is included by the reaction of formula ii compound and (s) -2- amino butanamide or its salt come formula
The compound of iv:
It will be appreciated by those skilled in the art that can by amide key-forming method known in the art with
By formula ii preparation of compounds of formula iv compound.
In above or other embodiment, can in the basic conditions, in organic solvent 1,
At a temperature of -20 DEG C -100 DEG C, make formula ii compound and (s) -2- amino butanamide or its reactant salt
Carry out formula iv compound, be wherein used for forming the use molar equivalent of the alkali of alkalescence condition in 1-5
Between, the use molar equivalent of (s) -2- amino-butanamide or its salt is between 0.5-5；Preferably,
Described alkali is selected from triethylamine, diisopropyl ethyl amine, pyridine, sodium hydroxide, potassium hydroxide, carbonic acid
Sodium, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine, two (front threes
Base silicon substrate) one of Lithamide. or two (trimethyl silicon substrate) Sodamide. or more kinds of, described organic
Solvent 1 be selected from oxolane, methyltetrahydrofuran, ether, dichloromethane, chloroform, acetonitrile, Isosorbide-5-Nitrae-
Dioxane, methanol, ethanol, isopropanol, n, n- dimethylformamide, n- methyl pyrrolidone,
One of dimethyl sulfoxide or more kinds of.
In other respects, the application provides a kind of method of formula v Bu Waxitan, methods described bag
Include and make formula iv compound cyclization synthesis type v Bu Waxitan:
It will be appreciated by those skilled in the art that can by nucleophilic displacement process known in the art with
By formula iv preparation of compounds of formula v compound Bu Waxitan.
In above or other embodiment, can in the basic conditions, in organic solvent 2,
At a temperature of -78 DEG C -100 DEG C, there is itself ring closure reaction formula v Bu Waxitan in the formula iv of making, its
In for formed alkalescence condition alkali use molar equivalent between 1-5；Preferably, described alkali choosing
From triethylamine, diisopropyl ethyl amine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, carbonic acid
Potassium, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine, two (trimethyl silicon substrates)
One of Lithamide. or two (trimethyl silicon substrate) Sodamide. or more kinds of, organic solvent 2 is selected from four
Hydrogen furan, methyltetrahydrofuran, ether, dichloromethane, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane,
Methanol, ethanol, isopropanol, n, n- dimethylformamide, n- methyl pyrrolidone, dimethyl sulfoxide
One of or more kinds of.
In a specific exemplary embodiment, methods described comprises the steps:
Compared with prior art, the application has the benefit that this for the method synthesizing Bu Waxitan
Synthetic route to prepare the Bu Waxitan of high-optical-purity by using the chiral raw material being easy to get, it is to avoid
Column chromatography purification etc. is unfavorable for the means of purification of industry's enlarging production, can obtain high-quality, high optics
The product (in four kinds of optical isomers, Bu Waxitan ratio is more than 99.5%) of purity, without using high
Expensive Chiral HPLC method splits, it is to avoid the waste for raw material for the chiral separation.By formula i chemical combination
Thing prepares the gross production rate about 40% of Bu Waxitan, higher than existing disconnecting route, and has optimization further to carry
The possibility rising.
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 formula ii compound
Anhydrous zinc chloride (2.5g, 18.3mmol) addition is had anti-in 20ml thionyl chloride
Answer in bottle, then by formula i compound (12.0g, 93.7mmol).Reaction bulb is placed in 55 DEG C of oil
React in bath, treat gas chromatographic detection (gas chromatographic detection) no starting material left, stopped reaction,
System is cooled to room temperature, screws out thionyl chloride, then the formula obtaining slightly yellow liquid through vacuum distillation
Ii compound, yield 68%.The nuclear magnetic data of formula ii compound is as follows: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 ii is: [α]23 d=+2.9 (c=10, chcl3)
Embodiment 2 formula ii compound
Anhydrous zinc chloride (40g, 0.29mol) is added the reaction having in 400ml thionyl chloride
In bottle, then by formula i compound (188g, 1.47mol).Reaction bulb is placed in 85 DEG C of oil baths
Reaction, treats gc detection no starting material left, stopped reaction, system is cooled to room temperature, screws out two
Chlorine sulfoxide, then the formula ii compound of slightly yellow liquid, yield 63.5% is obtained through vacuum distillation.
The nuclear magnetic data of formula ii compound 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 ii is: [α]23 d=+2.9 (c=10, chcl3)
Embodiment 3 formula iv compound
By formula iii compound (1.67g, 12mol) (purchased from Beijing coupling Science and Technology Ltd.)
Add in 40ml dry methylene chloride, add triethylamine (2.43g, 24mmol), under room temperature
After stirring 30 minutes, it is added dropwise over formula ii compound (2.0g, 10.8mmol), completion of dropping,
It is stirred at room temperature to tlc detection no starting material left.Add 30ml water, 4ml ethanol, extraction point
Go out organic faciess, be extracted twice with 40ml dichloromethane, merge organic faciess, anhydrous sodium sulfate is done
Dry, drying finishes, and filters, and filtrate is concentrated to give the crude product of formula iv compound, yield 96.7%.
Obtained after purification using column chromatography purification (developing solvent polarity: ethyl acetate 100%)
The nuclear magnetic data of formula iv compound is as follows:1H nmr (400mhz, cdcl3)δ6.20-6.45
(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 iv is: [α]25 d=-23.7 (c=3, ch3oh)
Embodiment 4 formula v compound
By method as described in Example 3 be obtained formula iv compound crude product 10.0g (with
40mmol counts), add and be dried in thf 150ml, by potassium tert-butoxide (5.6g, 50mmol)
Add in reaction bulb.System is reacted to tlc detection no starting material left, saturation chlorination at -30 DEG C
Ammonium is quenched reaction, separates organic faciess, and aqueous phase is extracted three times with 50ml ethyl acetate, is associated with
Machine phase, saturation nacl solution washed once, anhydrous sodium sulfate drying, filters, and filtrate concentrates
Obtain crude product, diisopropyl ether is pulled an oar, gained solid is Bu Waxitan, and yield 93%, through further
Recrystallization purifying can obtain high-purity product, the product of chiral hplc ＞ 99.5%.
The nuclear magnetic data of formula v compound is as follows:1H nmr (400mhz, cdcl3)δ6.45
(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 5 formula v compound
By method as described in Example 3 be obtained formula iv compound crude product 10.0g (with
40mmol count), add dry methylene chloride 150ml in, by tetrabutylammonium chloride (2.3g,
10mmol), anhydrous sodium sulfate (5.6g, 40mmol) adds in reaction bulb.Add solid koh
(4.2g, 75mmol) system is reacted to tlc detection no starting material left, saturation chlorine at -10 DEG C
Change ammonium and reaction is quenched, separate organic faciess, aqueous phase is extracted three times with 50ml dichloromethane, merge
Organic faciess, saturation nacl solution washed once, anhydrous sodium sulfate drying, filters, and filtrate is dense
Contract to obtain crude product, and diisopropyl ether is pulled an oar, and gained solid is Bu Waxitan, and yield 96%, through entering one
Step recrystallization purifying can obtain high-purity product, the product of chiral hplc ＞ 99.5%.
The nuclear magnetic data of formula v compound is as follows:1H nmr (400mhz, cdcl3)δ6.45
(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 6 formula iv compound
By formula iii compound (5.0g, 36mol) (purchased from Beijing coupling Science and Technology Ltd.)
Add 100ml to be dried in thf, add triethylamine (7.3g, 72mmol), stir under room temperature
After 30 minutes, it is added dropwise over formula ii compound (6.0g, 32.5mmol), completion of dropping, room
Temperature stirs to tlc detection no starting material left.Add 100ml water, separate organic faciess, use 50ml
Ethyl acetate extracts three times, merges organic faciess, anhydrous sodium sulfate drying, drying finishes, filters,
Filtrate is concentrated to give the crude product of formula iv compound.
Obtained after purification using column chromatography purification (developing solvent polarity: ethyl acetate 100%)
The nuclear magnetic data of formula iv compound is as follows:1H nmr (400mhz, cdcl3)δ6.20-6.45
(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 iv is: [α]25 d=-23.7 (c=3, ch3oh)
Embodiment 7 formula v compound
The crude product of the formula iv compound that method as described in Example 6 is obtained is (with 36mmol
Meter), add and be dried in thf 100ml, potassium tert-butoxide (4.8g, 43.2mmol) is added anti-
Answer in bottle.System is reacted to tlc detection no starting material left at 0 DEG C, and saturated ammonium chloride is quenched instead
Should, separate organic faciess, aqueous phase is extracted three times with 50ml ethyl acetate, merge organic faciess, satisfy
Washed once with nacl solution, anhydrous sodium sulfate drying, filter, filtrate is concentrated to give crude product,
Diisopropyl ether is pulled an oar, and it is solid that gained solid obtains formula v compound as white using isopropyl acetate recrystallization
Body, i.e. Bu Waxitan, together with 2 liang of step total recoverys 49% of embodiment, chiral hplc is pure
Degree ＞ 99.5%.
The nuclear magnetic data of formula v compound is as follows:1H nmr (400mhz, cdcl3)δ6.45
(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 8 formula i compound
Feldalat NM (2.05g, 38mmol) is added dissolving in 80ml dehydrated alcohol complete.
Reaction bulb is placed in ice-water bath, adds diethyl malonate.Stir 10 points at this temperature
Clock, system is warmed to room temperature, and is slowly added to (r)-epoxychloropropane (ee 98%) in reaction system
(2.7ml, 35mmol) (purchased from pacifying resistance to Jilin Chemical), finishes, reacts under system counterflow conditions
18 hours, stopped reaction, system is cooled to room temperature, is spin-dried for solvent, adds 100ml water,
Extracted 3 times with 100ml ethyl acetate.Merge organic faciess, anhydrous sodium sulfate drying, be dried
Finish, filter, filtrate is spin-dried for obtaining compound vi, obtains colourless liquid, yield through vacuum distillation
55%.Compound vi chirality hplc (ee 98%).
Cui (9.5g, 50mol) addition 100ml is dried in 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 be obtained to the such as said method of Deca in reaction bulb
Compound vi (20g, 117mmol) thf solution is dried.Completion of dropping, here temperature
After the lower stirring of degree 30 minutes, it is to slowly warm up to -15 DEG C.Reaction is quenched with saturated ammonium chloride, plus
Enter 1l water, extracted three times with 1l ethyl acetate, merging organic faciess, anhydrous sodium sulfate drying,
Drying finishes, and filters, and filtrate is concentrated to give compound vii crude product.It is added into dmso/h2o
(400ml/20ml), licl (14.7g, 350mmol) is added in reaction bulb.System exists
After 140 DEG C of reaction 18h, it is poured in 400ml water, extracts three with 400ml ethyl acetate
Secondary, merge organic faciess, saturation nacl solution washed once, anhydrous sodium sulfate drying, filter,
Filtrate is concentrated to give crude product, and vacuum distillation obtains compound i, colourless liquid, yield 50%.
The nuclear magnetic data of compound i 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 i 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 (12)
1. a kind of compound, described compound has a structure of formula ii:
2. a kind of method for preparing compound as claimed in claim 1, methods described includes
Step by formula i preparation of compounds of formula ii compound:
3. method according to claim 2, wherein 0 DEG C arrive backflow at a temperature of it is preferable that
At a temperature of between 55 DEG C -80 DEG C, in zncl2In the presence of, make thionyl chloride and formula i compound
Reaction；Preferably, thionyl chloride simultaneously as reaction solvent and thionyl chloride use molar equivalent
Between 1-50, it is highly preferred that the use molar equivalent of described thionyl chloride is between 2-5.
4. according to the method in claim 2 or 3, wherein, by following formula i compound:
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.
5. method according to claim 4, wherein,
By formula vi preparation of compounds of formula vii compound:
At a temperature of -78 DEG C to 200 DEG C, in aprotic organic solvent, make formula vi compound with
Ethyl metal reagent reacts formula vii compound, the wherein use molar equivalent of ethyl metal reagent
Between 1-5；Preferably, described ethyl metal reagent be selected from ethylmagnesium bromide, ethylmagnesium chloride,
One of diethyl zinc, ethyl-lithium and lead diethide or more kinds of；It is highly preferred that described ethyl gold
Belong to reagent to be used in combination with Hydro-Giene (Water Science)., Cupricin. or anhydrous zinc chloride, Hydro-Giene (Water Science). in reaction,
The use molar equivalent of Cupricin. or anhydrous zinc chloride is between 0.01-2；Preferably, described non-matter
Sub- organic solvent is selected from oxolane (thf), methyltetrahydrofuran, toluene, dichloromethane, ether
With one of methyl tertiary butyl ether(MTBE) or more kinds of；
By formula vii preparation of compounds of formula i compound:
In the mixture with water for the water miscible high boiling organic solvent, in the presence of salt or alkali,
Formula vii compound experience takes off ester group is made to be reacted to give formula i chemical combination within the temperature range of 50 DEG C -200 DEG C
The use molar equivalent of thing, wherein salt or alkali is between 0.01-10；Preferably, described salt is selected from chlorine
Change one of lithium, sodium chloride, potassium chloride, magnesium chloride and lithium bromide or more kinds of, described alkali is selected from
One of Lithium hydrate, potassium hydroxide or sodium hydroxide or more kinds of, described water miscible high boiling point
Organic solvent is selected from n- methyl pyrrolidone, n, n- dimethylformamide, dimethyl sulfoxide, sulfolane
With one of 4- methyl -2- amylalcohol or more kinds of；
If or, r contains unsaturated part, formula vii compound is made to first pass through metal catalytic removing
R group, then obtains formula i compound through decarboxylic reaction within the temperature range of 25 DEG C -200 DEG C；Excellent
Selection of land, described deacidification reaction is selected from toluene, methyl tertiary butyl ether(MTBE), n- methyl pyrrolidone, n, n-
Carry out in one or more of dimethylformamide and dimethyl sulfoxide.
6. compound as claimed in claim 1 is used for the purposes of synthesis type v Bu Waxitan
7. a kind of compound, described compound has a structure of formula iv:
8. a kind of method for preparing compound as claimed in claim 7, methods described includes leading to
Prepared by the reaction crossing compound as claimed in claim 1 with (s) -2- amino butanamide or its salt
The compound of formula iv:
9. method according to claim 8, wherein in the basic conditions, in organic solvent 1
In, at a temperature of -20 DEG C -100 DEG C, make formula ii compound and (s) -2- amino butanamide or its
Reactant salt carrys out formula iv compound, is wherein used for forming the use molar equivalent of the alkali of alkalescence condition
Between 1-5, the use molar equivalent of (s) -2- amino-butanamide or its salt is between 0.5-5；Excellent
Selection of land, described alkali be selected from triethylamine, diisopropyl ethyl amine, pyridine, sodium hydroxide, potassium hydroxide,
Sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine, two (three
Methylsilyl) one of Lithamide. or two (trimethyl silicon substrate) Sodamide. or more kinds of, described have
Machine solvent 1 be selected from oxolane, methyltetrahydrofuran, ether, dichloromethane, chloroform, acetonitrile,
Isosorbide-5-Nitrae-dioxane, methanol, ethanol, isopropanol, n, n- dimethylformamide, n- crassitude
One of ketone, dimethyl sulfoxide or more kinds of.
10. a kind of method of formula v Bu Waxitan, methods described includes making as claim 7 institute
The compound cyclization synthesis type v Bu Waxitan stating:
11. methods according to claim 10, wherein, in the basic conditions, in organic solvent
In 2, at a temperature of -78 DEG C -100 DEG C, there is itself ring closure reaction formula v cloth watt in the formula iv of making
Western smooth, wherein it is used for forming the use molar equivalent of the alkali of alkalescence condition between 1-5；Preferably,
Described alkali is selected from triethylamine, diisopropyl ethyl amine, pyridine, sodium hydroxide, potassium hydroxide, carbonic acid
Sodium, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine, two (front threes
Base silicon substrate) one of Lithamide. or two (trimethyl silicon substrate) Sodamide. or more kinds of, organic solvent
2 are selected from oxolane, methyltetrahydrofuran, ether, dichloromethane, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxy
Six rings, methanol, ethanol, isopropanol, n, n- dimethylformamide, n- methyl pyrrolidone, diformazan
One of base sulfoxide or more kinds of.
A kind of 12. methods of formula v Bu Waxitan, methods described comprises the steps:
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510430387.9A CN106365986B (en) | 2015-07-21 | 2015-07-21 | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan |
| CA2984832A CA2984832A1 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| KR1020177037062A KR102630456B1 (en) | 2015-05-25 | 2016-05-24 | Method of manufacturing 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 |
| BR112017025266A BR112017025266A2 (en) | 2015-05-25 | 2016-05-24 | process to produce brivaracetam |
| EP16800643.5A EP3302441B1 (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 |
| 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 |
| 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 |
| US16/256,522 US20190152908A1 (en) | 2015-05-25 | 2019-01-24 | Processes to produce brivaracetam |
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| CN201510430387.9A CN106365986B (en) | 2015-07-21 | 2015-07-21 | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan |
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| CN106432030A (en) * | 2015-10-10 | 2017-02-22 | 苏州鹏旭医药科技有限公司 | Preparation method of brivaracetam |
| 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 |
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| CN109593055A (en) * | 2017-09-30 | 2019-04-09 | 上海医药工业研究院 | A kind of preparation method of Bu Waxitan isomers (2S, 4S) |
| CN112110843A (en) * | 2019-06-20 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | Novel preparation method of brivaracetam |
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| WO2021260721A1 (en) * | 2020-06-23 | 2021-12-30 | Clininvent Research Pvt. Ltd. | A new cost effective and scalable process for synthesizing pure brivaracetam |
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Application publication date: 20170201 Assignee: CHENGDA PHARMACEUTICALS Co.,Ltd. Assignor: SUZHOU PENGXU PHARMATECH Co.,Ltd. Contract record no.: X2021980001583 Denomination of invention: Compound, its preparation method and application in the synthesis of buwasitan Granted publication date: 20190108 License type: Common License Record date: 20210311 |