CN109134341A - A kind of preparation method of Levetiracetam - Google Patents
A kind of preparation method of Levetiracetam Download PDFInfo
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- CN109134341A CN109134341A CN201811099818.8A CN201811099818A CN109134341A CN 109134341 A CN109134341 A CN 109134341A CN 201811099818 A CN201811099818 A CN 201811099818A CN 109134341 A CN109134341 A CN 109134341A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The present invention relates to technical field of medicine synthesis, provide a kind of preparation method of Levetiracetam, this method comprises: carrying out esterification using C4H9NO2 as starting material with thionyl chloride and obtaining (S) -2-amino-butyric acid methyl ester hydrochloride；(S) -2-amino-butyric acid methyl ester hydrochloride and ammonium hydroxide carry out aminolysis reaction generation (S) -2- amino-butanamide hydrochloride；(S) mixed solution of -2- amino-butanamide hydrochloride and 4- chlorobutanoylchloride and methylene chloride carries out acylation reaction；Subsequent intermediate product directly carries out ring closure reaction with methylene chloride and tetrabutylammonium bromide, obtains crude levetiracetam；Levetiracetam is generated through recrystallization.The preparation method uses the starting material being easy to get, it is ensured that synthetic route favorable reproducibility, unit is easy to operate, business accounting.Each step reaction is easy to purify, and quality controllable, reaction yield improves a lot.
Description
Technical field
The present invention relates to technical field of medicine synthesis, in particular to a kind of preparation method of Levetiracetam.
Background technique
The epilepsy disease curative as the second largest hardly possible for being only second to cerebrovascular disease, drastically influences the health of the mankind.According to
Statistics, has millions of people to suffer from epilepsy every year.Therefore, the mechanism of action is special, works rapidly, has excellent tolerance and safety
Antiepileptic have wide development potentiality.
Levetiracetam (Levetiracetam), the antiepileptic developed first when being excellent than drugmaker (USB),
Bioavilability is higher, and pharmacokinetics is linear, and protein binding rate is low, and is metabolized independent of liver cell pigment P450 etc., makes it
As compared with safe drugs.Chemical name: (S)-alpha-ethyl-2-oxo -1- pyrrolidine acetamide, molecular formula: C8H14N2O2, molecule
Amount: 170.21, CAS:102767-28-2.Chemical structural formula is as follows:
United States Patent (USP) US4696943 reports a kind of synthetic method of Levetiracetam, and the route is with (S) -2- amino fourth
Amide is starting material, using ethyl alcohol as solvent, reacts to obtain (S)-N- [1 (amino carbonyl with 4- chlorobutanoylchloride under potassium carbonate effect
Base) propyl] -4- chlorobutamide, then the highly basic such as potassium hydroxide the effects of under cyclization generate Levetiracetam.The preparation method
The product purity of acquisition is not relatively high, and carbonyl α easily occurs racemization and generates enantiomter impurity, and in subsequent purifying not
It easily removes, influences product optical purity.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation method of Levetiracetam, which uses the starting being easy to get
Material, it is ensured that synthetic route favorable reproducibility, unit is easy to operate, business accounting.Reaction process of the present invention is easy to operate, and each step is anti-
It should be easy to purify, quality controllable, reaction yield improves a lot.
The embodiment of the present invention is achieved in that
A kind of preparation method of Levetiracetam comprising:
Step 1: using C4H9NO2 as starting material, carrying out esterification with thionyl chloride and obtain (S) -2- amino fourth
Acid methyl ester hydrochloride salt；
Step 2:(S) -2-amino-butyric acid methyl ester hydrochloride and ammonium hydroxide carries out aminolysis reaction generation (S) -2- amino-butanamide
Hydrochloride；
Step 3:(S) -2- amino-butanamide hydrochloride in methylene chloride, tetrabutylammonium bromide, anhydrous sodium sulfate and ties up acid
Under the conditions of agent is existing, acylation reaction generation (S)-N- [1 (amino is carried out with the mixed solution of 4- chlorobutanoylchloride and methylene chloride
Carbonyl) propyl] -4- bromine butyramide；
Step 4:(S)-N- [1 (amino carbonyl) propyl] -4- bromine butyramide and methylene chloride and tetrabutylammonium bromide, in nothing
Ring closure reaction is carried out under the conditions of aqueous sodium persulfate and potassium hydroxide, obtains crude levetiracetam；
Step 5: crude levetiracetam generates Levetiracetam through recrystallization.
The beneficial effect of the embodiment of the present invention is:
The preparation method of Levetiracetam provided in an embodiment of the present invention controls isomers based on finished product quality is guaranteed
Content, increase reaction step, use the starting material being easy to get, it is ensured that synthetic route favorable reproducibility, unit is easy to operate, economical
It calculates.Reaction process of the present invention is easy to operate, and each step reaction is easy to purify, and quality controllable, reaction yield improves a lot.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
The preparation method of the Levetiracetam of the embodiment of the present invention is specifically described below.
The present invention provides a kind of sides that Levetiracetam is synthesized using C4H9NO2 and thionyl chloride as starting material
Method.The preparation method includes the following steps:
Step 1: with C4H9NO2 (SM1-1) for starting material, carrying out esterification with thionyl chloride and obtain (S)-
2-amino-butyric acid methyl ester hydrochloride (SM1-2).Reaction equation such as formula (I).
1.1 (S) -2-amino-butyric acid methyl ester hydrochlorides synthesize material and ingredient proportion
| Name of material | Molal weight | Molal quantity | Proportion |
| C4H9NO2 | 103.12 | 484.8 | 0.85-1.20 |
| Methanol | —— | —— | 3.60-4.40 |
| Thionyl chloride | 118.97 | 630.4 | 1.25-1.75 |
| Acetone (is evaporated use) | —— | —— | 0.38-0.42 |
| Acetone (mashing is used) | —— | —— | 3.00-3.25 |
| Acetone (elution is used) | —— | —— | 0.38-4.15 |
1.2 (S) -2-amino-butyric acid methyl ester hydrochloride synthetic operation methods
The methanol for measuring recipe quantity is added in glass-lined reactor, opens agitating paddle, will weigh the L-2- amino of recipe quantity
Butyric acid is added in glass-lined reactor；Fluid temperature is cooled to 5~10 DEG C, the thionyl chloride for weighing recipe quantity is added dropwise to and is warded off
In glass reaction pot, process is added dropwise, fluid temperature is kept to be no more than 40 DEG C, drips and finish medical fluid clarification.Completion of dropwise addition, it is warming up to 60~
65 DEG C maintain the reflux for, and reaction carries out a TLC monitoring for every 30 minutes no less than after 2 hours, and the disappearance of C4H9NO2 spot is
Reaction terminates.Monitoring judges reaction end by the following method.
Reaction end monitoring method:
Inspection method: TLC method
Lamellae: GF254
Solvent: methanol: 3~10 drop triethylamines are added in methylene chloride=1:2；(ninhydrin is matched for ninhydrin solution colour developing
System: weighing 1.5g ninhydrin, is added to 100ml n-butanol, and 3ml acetic acid is added and mixes).
The preparation method of test liquid: the direct contact plate of reaction solution
Coloration method: after expansion, the heating colour developing of TLC plate
Wherein, evaporated under reduced pressure: end of reaction, medical fluid are oozed in 45~55 DEG C of evaporated under reduced pressure to solvent-free, and calculation amount is added
Acetone, stirring are not less than 15min, and medical fluid is oozed in 45~55 DEG C of evaporated under reduced pressure to solvent-free.
Mashing: reduced pressure terminates, and the acetone of calculation amount is added, and fluid temperature is controlled at 0~10 DEG C, and stirring is not less than 1
Hour.
Filtering: stirring terminates, and the suction filtration cylinder that medical fluid is installed additional filter cloth filters, and calculation amount is used when no continuous liquid flows out
Acetone eluted, filter to timing is no less than 30 minutes again without flowing continually out liquid；
Vacuum drying: it collects filter cake and is put into enamel pallet, be put into vacuum oven, vacuum degree control is in -0.08MPa
More than, it is no more than 35 DEG C of dryings to constant weight.Drying terminates, and collects white solid.
1.3 production process control methods and standard
Step 2:(S) -2-amino-butyric acid methyl ester hydrochloride (SM1-2) and ammonium hydroxide carries out aminolysis reaction generation (S) -2- amino
Butanamide hydrochloride (SM1)；Reaction equation such as formula (II).
2.1 (S) -2- amino-butanamide hydrochloride synthetic operation methods
The ammonium hydroxide for measuring recipe quantity is added in reaction kettle, opens agitating paddle, fluid temperature is down to -10~-5 DEG C, by several times
The previous step intermediate of calculation amount is added, keeps temperature control at -10~-5 DEG C during charging, under the conditions of -10~-5 DEG C
After being stirred to react 36 hours, a TLC monitoring is carried out within every 1 hour, previous step intermediate spot disappears to be terminated for reaction.By following
Method monitoring judges reaction end.
Reaction end monitoring method:
Inspection method: TLC method
Lamellae: GF254
Solvent: methanol: 3~10 drop triethylamines are added in methylene chloride=1:2；(ninhydrin is matched for ninhydrin solution colour developing
System: weighing 1.5g ninhydrin, is added to 100ml n-butanol, and 3ml acetic acid is added and mixes).
The preparation method of test liquid: the direct contact plate of reaction solution
Coloration method: after expansion, the heating colour developing of TLC plate
Evaporated under reduced pressure: end of reaction, medical fluid are oozed in 55~65 DEG C of evaporated under reduced pressure to solvent-free.
Primary mashing: reduced pressure terminates, and the acetone of calculation amount is added, and fluid temperature is controlled at 20~25 DEG C, and stirring is not
Lower than 1 hour, mashing terminated the suction filtration cylinder filtering that material is installed additional filter cloth, and filter cake recipe quantity acetone washing is filtered to nothing
Flowing continually out liquid, timing is no less than 30 minutes again.
Solid after suction filtration: being transferred to the acetone that calculation amount is added in reaction kettle by secondary mashing, and fluid temperature is controlled 20
~25 DEG C, stirring is not less than 1 hour.Using being beaten twice in the present embodiment, the purity of intermediate can be improved, be later period finished product
Crystal form and purity guarantee are provided.
Filtering: medical fluid through install additional filter cloth suction filtration cylinder filter, when no continuous liquid flows out using the acetone of calculation amount into
Row elution is filtered to the outflow of no continuous liquid, is continued suction filtration and is no less than 30min, collects filter cake.
Vacuum drying: collecting filter cake and be put into enamel pallet, be put into vacuum oven, and the control of setting drying box temperature is not
More than 40 DEG C, vacuum degree control is dry to constant weight more than -0.08MPa.Drying terminates, and collects white solid.
2.2 (S) -2- amino-butanamide hydrochlorides synthesize material and ingredient proportion
| Name of material | Molal weight | Molal quantity | Proportion |
| Previous step intermediate | 153.6 | 339.4 | 0.90-1.10 |
| Ammonium hydroxide | —— | —— | 3.50-3.70 |
| Acetone (primary mashing is used) | —— | —— | 1.8-2.10 |
| Acetone (primary elution is used) | —— | —— | 0.38-0.41 |
| Acetone (secondary mashing is used) | —— | —— | 1.85-2.10 |
| Acetone (secondary elution is used) | —— | —— | 0.38-4.10 |
2.3 production process control methods and standard
Step 3:(S) -2- amino-butanamide hydrochloride (SM1) methylene chloride, tetrabutylammonium bromide, anhydrous sodium sulfate and
Under the conditions of acid binding agent is existing, acylation reaction generation (S)-is carried out with the mixed solution (SM2) of 4- chlorobutanoylchloride and methylene chloride
N- [1 (amino carbonyl) propyl] -4- bromine butyramide (FLCS- II)；Reaction equation such as formula (III).
3.1 (S)-N- [1 (amino carbonyl) propyl] -4- bromine butyramide synthetic operation method
The methylene chloride for weighing calculation amount is added in reaction kettle, opens agitating paddle；The anhydrous sodium sulfate for weighing recipe quantity adds
Enter in reaction kettle, the previous step intermediate for weighing recipe quantity is added in reaction kettle；The tetrabutylammonium bromide for weighing recipe quantity is added
In reaction kettle；Fluid temperature -5~0 DEG C is controlled, the acid binding agent (such as potassium hydroxide) of calculation amount is slowly added to, during charging
Keep fluid temperature -5~0 DEG C；It finishes, controls fluid temperature -5~0 DEG C, stirring is not less than 1 hour；The SM2 of calculation amount is added dropwise
With methylene chloride mixed solution, fluid temperature -5~0 DEG C is kept during being added dropwise.Drop finishes, and keeps fluid temperature -5~0 DEG C, after
Continuous stirring 30min, sampling carry out TLC monitoring, and previous step intermediate spot disappears to be terminated for reaction.Monitoring judgement by the following method
Reaction end.Reaction system directly carries out next step production.
Reaction end monitoring method:
Inspection method: TLC method
Lamellae: GF254
Solvent: methanol: methylene chloride=1:5, (ninhydrin is prepared: being weighed 1.5g ninhydrin, is added for ninhydrin solution colour developing
Enter to 100ml n-butanol, 3ml acetic acid is added and mixes).
The preparation method of test liquid: the direct contact plate of reaction solution
Coloration method: after expansion, the heating colour developing of TLC plate
3.2 Levetiracetam acylation reaction materials and ingredient proportion
3.3 production process control methods and standard
In other embodiments, acid binding agent can also be sodium sulphate, potassium acid sulfate, sodium bicarbonate, sodium carbonate or carbonic acid
Hydrogen potassium.
Step 4:(S)-N- [1 (amino carbonyl) propyl] -4- bromine butyramide (FLCS- II) and methylene chloride and tetrabutyl bromine
Change ammonium, ring closure reaction is carried out under the conditions of anhydrous sodium sulfate and potassium hydroxide, obtains crude levetiracetam (FLCS- I)；Reaction
Formula such as formula (IV).
4.1 crude levetiracetam synthetic operation methods
The potassium hydroxide for weighing calculation amount, is slowly added in reaction kettle, and fluid temperature -5~0 DEG C is kept during charging；
It finishes, controls fluid temperature -5~0 DEG C, continue stirring 2 hours, sampling carries out TLC monitoring, and the disappearance of previous step intermediate spot is
Reaction terminates.Monitoring judges reaction end by the following method.Reaction system directly carries out next step production.
Reaction end monitoring method:
Inspection method: TLC method
Lamellae: GF254
Solvent: acetone: ethyl acetate=1:3, (ninhydrin is prepared: being weighed 1.5g ninhydrin, is added for ninhydrin solution colour developing
Enter to 100ml n-butanol, 3ml acetic acid is added and mixes).
The preparation method of test liquid: the direct contact plate of reaction solution
Coloration method: after expansion, the heating colour developing of TLC plate
Filtering: reaction terminates, and controls fluid temperature -5~0 DEG C, is slowly added to calculate glacial acetic acid, the silicon of calculation amount is added
Glue, continues to stir 30min, filters out solid using the suction filtration cylinder through installing filter cloth and filter paper additional, collects medical fluid.
Washing filtering: collecting solid, solid be transferred in reaction kettle, and calculation amount methylene chloride is added, and controls medical fluid temperature
- 5~0 DEG C of agitator treating of degree is not less than 15 minutes, filters out solid using the suction filtration cylinder through installing filter cloth and filter paper additional, filters to without even
Medical fluid is collected in continuous liquid outflow, is collected medical fluid, is repeated aforesaid operations 1 time, merging filtrate；It is slowly added to calculate glacial acetic acid.
Evaporated under reduced pressure: medical fluid is oozed in 35~40 DEG C of evaporated under reduced pressure to solvent-free, and the ethyl acetate of calculation amount is added, and is continued
Evaporated under reduced pressure is oozed to solvent-free.
Mashing: reduced pressure terminates, and the ethyl acetate of calculation amount is added, and fluid temperature is controlled at 10~15 DEG C, and stirring is not
Lower than 30min.
Filtering: stirring terminates, and medical fluid uses the suction filtration cylinder through installing filter cloth additional to be filtered, and makes when no continuous liquid flows out
It is eluted, is filtered to the outflow of no continuous liquid with the ethyl acetate for being cooled to 10~15 DEG C of calculation amount, continue to filter not
Less than 30min, filter cake is collected.
Vacuum drying: collecting filter cake and be put into enamel pallet, be put into vacuum oven, and the control of setting drying box temperature is not
More than 40 DEG C, vacuum degree control is dry to constant weight more than -0.08MPa.Drying terminates, and collects white solid.
4.2 Levetiracetams synthesize material and ingredient proportion
4.3 production process control methods and standard
Step 5: crude levetiracetam (FLCS- I) generates Levetiracetam (I highly finished product of FLCS-) through recrystallization；Reaction
Formula such as formula (V).
5.1 Levetiracetam highly finished product synthetic operation methods
It weighs the previous step intermediate of calculation amount, is added into reaction kettle, weigh the first solvent (such as third of calculation amount
Ketone), it is added in reaction kettle；Turn on agitator, fluid temperature are controlled at 55~60 DEG C, are maintained the reflux for, and stir dissolved clarification.
Filtering: after medical fluid dissolved clarification, medical fluid is filtered through 2 filter paper, collects medical fluid.
Evaporated under reduced pressure: medical fluid is oozed in 35~40 DEG C of evaporated under reduced pressure to solvent-free.
Absorption: evaporated under reduced pressure terminates, and the acetone water mixed solution of calculation amount is added, and fluid temperature is controlled at 45~50 DEG C,
Dissolved clarification is stirred, the active carbon of calculation amount is added, fluid temperature is controlled at 45~50 DEG C, stirring and adsorbing 1 hour.
Filtering: active carbon stirring and adsorbing terminates, and medical fluid adds 1 0.45 μm of organic membrane filter through 2 filter paper, collects medical fluid.
Crystallization: fluid temperature -30~-20 DEG C stand crystallization after control filtering, and observation is opened after having a large amount of crystal to be precipitated and stirred
Device is mixed, stirring and crystallizing is not less than 12 hours.Compared to crystallization is carried out at -5~30 DEG C, selection is -30~-20 in the present embodiment
Yield can be improved in DEG C crystallization, guarantees crystal form quality, is conducive to later period production collection processing.
Centrifugation: crystallization terminates, and medical fluid is transferred in centrifuge and is centrifuged, and after centrifugation to no continuous liquid outflow, continues
Centrifugation is no less than 30min, collects filter cake.
Vacuum drying: collecting filter cake and be put into enamel pallet, be put into vacuum oven, and the control of setting drying box temperature is not
More than 35 DEG C, vacuum degree control is dry to constant weight more than -0.08MPa.Drying terminates, and collects white solid.
It should be understood that first solvent is ketone, tetrahydrofuran or the acetonitrile of C3-C6 in other embodiments of the invention
One of or it is a variety of；Preferably, the ketone of C3-C6 include acetone, butanone, methylisobutylketone, 2 pentanone, propione, 3- oneself
One of ketone is a variety of.
5.2 Levetiracetams refine material and ingredient proportion
5.3 production process control methods and standard
The preparation method further progress of Levetiracetam of the invention is illustrated with reference to embodiments.
Embodiment 1
Present embodiments provide a kind of preparation method of Levetiracetam comprising following steps:
Step 1: esterification
Addition C4H9NO2 18kg (174.55mol), anhydrous methanol 90L (5v/w) into 500L reactor, 25 DEG C
Lower dropwise addition thionyl chloride 27.0kg (226.9mol), probably dropwise addition 1h, control temperature are no more than 40 DEG C, and solution becomes molten from muddiness
Clearly.It is added dropwise, temperature rising reflux reacts 2h, and (point sample 1 time, solvent: methylene chloride/methanol=2/1 adds 3 three second of drop for TLC detection
Amine, RfSM1-1=0.3, RfSM1-2=0.9), it reacts and finishes 50 DEG C of evaporating solvent under reduced pressure, done using 9L (0.5v/w) acetone band residual
Stay solvent；It is spin-dried for object and 10 DEG C of mashing 1h of 72L (4v/w) acetone is added, filtering is eluted with 9L (0.5v/w) acetone.35 DEG C of filter cake subtract
It press dry dry to constant weight, obtains white solid (SM1-2) 18769.3g, yield 70%.
Step 2: ammonolysis reaction
Ammonium hydroxide 74.8L (4v/w) is added into 500L reactor, stirring is cooled to -10~-5 DEG C, and SM1-2 is added
18.7kg (121.74mol), control temperature -10 DEG C~-5 DEG C reactions 36h, TLC monitor (solvent: methylene chloride/methanol=2/
1 plus 3 drop triethylamines, RfSM1-2=0.8, RfSM1=0.6), 60 DEG C of evaporating solvent under reduced pressure of end of reaction (screw out 70% or so
Water v/v), it is spin-dried for object and 10 DEG C of mashing 1h, 9L (0.5v/w) acetone elution filter cakes of 56L (3v/w) acetone is added；Filter cake 56L (3v/
W) it is beaten 1h again for 10 DEG C of acetone, 9L (0.5v/w) acetone elutes filter cake.Filtering, 35 DEG C of filter cake are dried under reduced pressure to constant weight, obtain
White solid (SM1) 14848g, yield 88%.
Step 3: acylation reaction
To 500L reactor methylene chloride 262.7kg, anhydrous sodium sulfate 18250.0g (128.5mol), tetrabutylammonium bromide
1.73kg (5.37mol), SM1 14840.0g (106.8mol), stir and evenly mix, are cooled to -5 DEG C or so, be directly added into KOH
(95%) powder 17.99kg (320.7mol) (0 DEG C of temperature control or so, heating is not apparent), finishes, temperature is down to -5 DEG C of left sides
19625.0g SM2 and 31.16kg methylene chloride mixed liquor, control temperature -5~0 DEG C is added dropwise in the right side (heating is obvious).About 2h is added dropwise
Finish, direct sample 1mL methylene chloride dilution after TLC detection (point sample 1 time, solvent: methylene chloride/methanol=5/1, RfI=
0.5, RfII=0.7), reaction is finished.
Step 4: ring closure reaction
Divide equally criticize three times into above-mentioned reaction system be added KOH (95%) powder 17.99kg (320.7mol) (temperature control is 0
DEG C or so) about 1h, react 2h for control temperature -5~0 DEG C, sampling 1mL methylene chloride dilution TLC monitoring (point sample 1 time, solvent:
Ethyl acetate/acetone=3/1, RfI=0.5, RfII=0.7), reaction is finished, and 11.28kg glacial acetic acid is added in three times, and (temperature control is 0
DEG C or so), 22.2kg silica gel stirs 1h, filtering, and 1.04kg glacial acetic acid tune pH value is added to faintly acid in filtrate.35 DEG C of filtrate subtract
Ethyl acetate 14.84L concentration is added into residual solid object and is spin-dried for, is added 25 DEG C of 7.42L ethyl acetate to solid and beats for pressure concentration
1h, filtering are starched, 3L ethyl acetate elutes 45 DEG C of forced air dryings of solid to constant weight, obtains crude levetiracetam 12.7kg, crude product is received
Rate 70%.
Step 5: purification
Crude levetiracetam 12500g is added into 100L reactor, 62.5L (5v/w) acetone is heated to reflux to whole
Dissolution, is filtered while hot, and 35 DEG C are spin-dried for filtrate, and all molten of 50L acetone/water (20:1,4v/w) 45 DEG C of heating is added into solid
Solution, is added 625g active carbon and stirs 1h, and crossing 0.45 μm of filter membrane while hot, (solvent can volatilize, and filters pressing may cause yield and be dropped
It is low), filtrate puts -20 DEG C of crystallization 16h, and filtering is placed 35 DEG C and is dried under reduced pressure to constant weight, and white crystal 10kg is obtained, and refines yield
80.6%.
Embodiment 2
Present embodiments provide a kind of preparation method of Levetiracetam comprising following steps:
Step 1: esterification
Methanol (8.1L, 5.0v/w) is added in reaction flask, is added with stirring C4H9NO2 1.62kg (1.00eq), 5-
Under the conditions of 10 DEG C, thionyl chloride 2.43kg (1.3eq) is added dropwise into reaction flask, reaction heating (note: has hydrogen chloride gas when dropwise addition
It generates, device for absorbing tail gas).Drop finishes, reaction system clarification.It is warming up to reflux, is reacted 2-3 hours, (solvent: first is controlled in TLC
Alcohol+2 drips triethylamine, ninhydrin colour developing).SM1-1 end of reaction is concentrated under reduced pressure, solvent-free to steam, and acetone 8.1L (5v/ is added
W), it stirs 30 minutes for 25 DEG C, filtering, 50 DEG C of filter cake are dried under reduced pressure 5 hours, vacuum degree -0.85--0.1MPa.Obtain white solid
1.56kg, yield 64.7%, purity 97.54%.
Step 2: ammonolysis reaction
Ammonium hydroxide 6.0L (4.0v/w) is added in reaction flask, cools down, stirring.In -10 DEG C -- SM1- is added portionwise under the conditions of 5 DEG C
2 1.50kg (1.00eq), finish, stirring to dissolved clarification, stir 36 hours under the conditions of -10--5 DEG C.(solvent: methanol is controlled in TLC
+ 2 drop triethylamines, ninhydrin colour developing).End of reaction is concentrated under reduced pressure, 50-60 DEG C of temperature, vacuum degree -0.085--0.1MPa.It is dense
Be reduced to it is solvent-free distillate, be added acetone 3.5L (2.33v/w), 25 DEG C stir 30 minutes, be filtered to remove solvent.Filter cake acetone
3.5L (2.33v/w) continues to be beaten, and 25 DEG C are stirred 30 minutes, filtering.45 DEG C of filter cake are dried under reduced pressure 16 hours.Obtain 1.1kg white
Powder, yield 81.70%, purity 86.89%.
Step 3: acylation reaction
It in 20L reaction flask, is added methylene chloride 8.9kg (17.7w/w), anhydrous sodium sulfate 600g is added in stirring
(1.2eq), SM1 500.0g (1.0eq) are added tetrabutylammonium bromide 58.5g (0.05eq).- 5 DEG C are cooled to, hydroxide is added
Potassium 606.0g (3.0eq)；Under the conditions of -5-0 DEG C, SM2 is added dropwise into reaction kettle (661.2g is dissolved in 1.0kg methylene chloride).
Drop finishes, and stirs 0.5 hour under the conditions of -5-0 DEG C of holding, TLC monitoring reaction, (ethanol/methylene 1/5), and ninhydrin high temperature is aobvious
Color.SM1 fundamental reaction is complete, and reaction system directly uses.
Step 4: ring closure reaction
Potassium hydroxide 606.0g (3.0eq) is added in reaction system in five batches one step up；It finishes, -5-0 DEG C of heat preservation stirrings
It 2 hours, is controlled in TLC, (acetone/ethyl acetate 1/3), ninhydrin colour developing.Glacial acetic acid is added in intermediate FLCS-II fully reacting
260.0g (0.43w/w) is stirred 30 minutes, and solution is separated with solid.Filtering supernatant collects filtrate.35-40 DEG C of temperature control, very
Reciprocal of duty cycle -0.085--0.1MPa, filtrate decompression concentration are dry.750.0mL ethyl acetate is added, under the conditions of 25 DEG C, stirs 30 minutes,
It is filtered to remove filtrate.Filter cake is at 50 DEG C, and forced air drying 10 hours.Obtain white crystal 441.0g, two step yields 71.71%.
Step 5: purification
Acetone 2.2L (5.0v/w) is added in reaction flask, is heated to flowing back, stirring to dissolved clarification.Filtrate, decompression are collected in filtering
It is concentrated (40-45 DEG C of temperature control, vacuum degree-0.085-0.1MPa).Concentration is dry, is added 1.76L acetone/water (20:1) (4v/w), rises
To 45 DEG C, stirring and dissolving is added active carbon 22.0g (5%w/w) temperature, keeps the temperature 45 DEG C and stirs 1 hour, excessively 0.45um filter membrane, and -20
DEG C freezing stirring and crystallizing 12 hours.Supernatant is poured out, solid is taken, 35 DEG C are dried in vacuo 12 hours.White crystals 266.5g is obtained, is received
Rate 60.43%.Purity 99.97%.
The preparation method of Levetiracetam provided in an embodiment of the present invention controls isomers based on finished product quality is guaranteed
Content, increase reaction step, use the starting material being easy to get, it is ensured that synthetic route favorable reproducibility, unit is easy to operate, economical
It calculates.Reaction process of the present invention is easy to operate, and each step reaction is easy to purify, and quality controllable, reaction yield improves a lot.We
Method reaches that reaction condition is mild, and unit safety easy to operate, synthesis material is easy to get, intermediate ring by adjusting starting material and alkali
Save it is quality controllable, it is at low cost to can be effectively controlled single miscellaneous (especially enantiomter).
These are only the preferred embodiment of the present invention, is not intended to restrict the invention, for those skilled in the art
For member, the invention may be variously modified and varied.All within the spirits and principles of the present invention, it is made it is any modification,
Equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Levetiracetam, characterized in that it comprises:
Step 1: using C4H9NO2 as starting material, carrying out esterification with thionyl chloride and obtain (S) -2-amino-butyric acid first
Ester hydrochloride；
Step 2:(S) -2-amino-butyric acid methyl ester hydrochloride and ammonium hydroxide carries out aminolysis reaction generation (S) -2- amino-butanamide hydrochloric acid
Salt；
Step 3:(S) -2- amino-butanamide hydrochloride deposits in methylene chloride, tetrabutylammonium bromide, anhydrous sodium sulfate and acid binding agent
Under the conditions, acylation reaction generation (S)-N- [1 (amino carbonyl) is carried out with the mixed solution of 4- chlorobutanoylchloride and methylene chloride
Propyl] -4- bromine butyramide；
Step 4:(S)-N- [1 (amino carbonyl) propyl] -4- bromine butyramide and methylene chloride and tetrabutylammonium bromide, in anhydrous sulphur
Ring closure reaction is carried out under the conditions of sour sodium and potassium hydroxide, obtains crude levetiracetam；
Step 5: crude levetiracetam generates Levetiracetam through recrystallization.
2. the preparation method of Levetiracetam according to claim 1, which is characterized in that in step 1, in the L-2-
Before aminobutyric acid is reacted with the thionyl chloride, first by the greenhouse cooling of the C4H9NO2 to 5~10 DEG C；
Preferably, when the thionyl chloride is added dropwise, the temperature of medical fluid is maintained to be no more than 40 DEG C, after completion of dropwise addition, in 60~65
DEG C carrying out being back to reaction terminates；After reaction, medical fluid is dried under vacuum to constant weight after evaporated under reduced pressure, mashing filtering；
Preferably, evaporated under reduced pressure includes first oozing medical fluid to solvent-free in 45-55 DEG C of evaporated under reduced pressure removal solvent, is subsequently added into
Calculation amount acetone, stirs 15-30min, and medical fluid continuation is oozed in 45-55 DEG C of evaporated under reduced pressure to solvent-free；
Preferably, after mashing filtering is included in evaporated under reduced pressure, acetone is added, stirring to pulp then filters, and then uses acetone
It is eluted, is filtered；
Preferably, in stirring to pulp, fluid temperature is controlled at 0-10 DEG C, and stirring is not less than 1 hour；
Preferably, it when filtering, filters to without liquid is flowed continually out, timing is no less than 30 minutes again；
Preferably, in vacuum drying, vacuum degree is greater than -0.08MPa, and drying temperature is no more than 35 DEG C.
3. the preparation method of Levetiracetam according to claim 1, which is characterized in that in step 2, add into ammonium hydroxide
Enter (S) -2-amino-butyric acid methyl ester hydrochloride, being stirred to react under the conditions of -10~-5 DEG C to reaction terminates, then by medical fluid
Evaporated under reduced pressure, twice mashing filtering are carried out, constant weight is then dried under vacuum to；
Preferably, evaporated under reduced pressure includes oozing medical fluid to solvent-free in 55~65 DEG C of evaporated under reduced pressure；
Preferably, after mashing filtering twice includes: evaporated under reduced pressure, acetone is added and carries out a stirring to pulp, then filters
And acetone is added into filter cake and carries out once washing, it then filters and acetone progress secondary agitation is added to solid after suction filtration and beat
Slurry, then filtering and the secondary elution of addition acetone progress into filter cake, filter and collect filter cake；
Preferably, in the herb liquid temperature control of mashing filtering twice at 20~25 DEG C, stirring is not less than 1 hour；
Preferably, in vacuum drying, vacuum degree is greater than -0.08MPa, and drying temperature is no more than 40 DEG C.
4. the preparation method of Levetiracetam according to claim 1, which is characterized in that in step 3, dichloro is first added
Methane is subsequently added into anhydrous sodium sulfate, (S) -2- amino-butanamide hydrochloride and tetrabutylammonium bromide, hydroxide is then added
The mixed solution of 4- chlorobutanoylchloride and methylene chloride is added dropwise in potassium after stirring, continuing stirring to reaction terminates；
Preferably, in entire reaction, keeping fluid temperature is -5~0 DEG C.
5. the preparation method of Levetiracetam according to claim 1, which is characterized in that in step 3, the acid binding agent
For sodium sulphate, potassium acid sulfate, potassium hydroxide, sodium bicarbonate, sodium carbonate or saleratus.
6. the preparation method of Levetiracetam according to claim 1, which is characterized in that ring closure reaction in step 4
Afterwards, glacial acetic acid and silica gel are added into medical fluid, agitation and filtration collects filtrate, and glacial acetic acid is added into filtrate, evaporated under reduced pressure
Afterwards, ethyl acetate is added, continues evaporated under reduced pressure, ethyl acetate is added, stirring, then mashing filtering, is drenched with ethyl acetate
Filter wash cake, filter cake is dried in vacuo after filtering；
Preferably, in addition glacial acetic acid and silica gel into medical fluid, agitation and filtration, fluid temperature is -5~0 DEG C；
Preferably, the temperature of evaporated under reduced pressure is 35~40 DEG C；
It preferably, is 10~15 DEG C in the temperature of mashing filtering herb liquid.
7. the preparation method of Levetiracetam according to claim 6, which is characterized in that glacial acetic acid is being added into filtrate
It further include that methylene chloride is added into the solid that filtering obtains before carrying out evaporated under reduced pressure, control fluid temperature is -5~0 DEG C,
It is filtered after agitator treating, collects filtrate；It is primary to repeat operation, then ice is added into combined mixed filtrate in merging filtrate
Acetic acid.
8. the preparation method of Levetiracetam according to claim 1, which is characterized in that in steps of 5, to the left second
The first solvent, temperature rising reflux to solution dissolved clarification are added in La Xitan crude product；Filter and by medical fluid evaporated under reduced pressure, be subsequently added into acetone
Aqueous solution after stirring dissolved clarification, is added active carbon stirring and adsorbing, filters and collect filtrate, then filtrate is cooled to -30~-20 DEG C
Crystallization after crystallization, medical fluid is carried out filter cake is collected after centrifugation, filter cake is dried under vacuum to constant weight.
9. the preparation method of Levetiracetam according to claim 8, which is characterized in that in steps of 5, described first is molten
Agent is one of ketone, tetrahydrofuran or acetonitrile of C3-C6 or a variety of；Preferably, the ketone of the C3-C6 include acetone,
One of butanone, methylisobutylketone, 2 pentanone, propione, 3- hexanone are a variety of.
10. the preparation method of Levetiracetam according to claim 8, which is characterized in that in steps of 5, filtrate is cold
But extremely -30~-20 DEG C of crystallizations stand crystallization at including: prior to -30~-20 DEG C, after having crystal precipitation, are stirred crystallization,
The stirring and crystallizing time is not less than 12h；
Preferably, the volume/weight ratio of the aqueous acetone solution of addition and the product after evaporated under reduced pressure is 3-5:1；Described third
The volume ratio of acetone and water is 20-30:1 in ketone aqueous solution；
Preferably, after the amount and dissolved clarification of the active carbon of addition the amount of medical fluid 4%-6%.
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| CN110698379A (en) * | 2019-11-19 | 2020-01-17 | 湖南洞庭药业股份有限公司 | Process for the preparation of levetiracetam |
| CN111004138A (en) * | 2019-12-12 | 2020-04-14 | 南京恒道医药科技有限公司 | Green production method and device of levetiracetam key intermediate S-2-methyl aminobutyric acid |
| CN111440083A (en) * | 2020-04-30 | 2020-07-24 | 贵州联科中贝制药科技有限公司 | Preparation method of (S) - (+) -2-aminobutanamide hydrochloride |
| CN114560800A (en) * | 2022-03-03 | 2022-05-31 | 吉林省博大制药股份有限公司 | Production method of levetiracetam bulk drug |
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| CN111004138A (en) * | 2019-12-12 | 2020-04-14 | 南京恒道医药科技有限公司 | Green production method and device of levetiracetam key intermediate S-2-methyl aminobutyric acid |
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