CN103159661A - Preparation method of levetiracetam - Google Patents
Preparation method of levetiracetam Download PDFInfo
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- CN103159661A CN103159661A CN2011104115481A CN201110411548A CN103159661A CN 103159661 A CN103159661 A CN 103159661A CN 2011104115481 A CN2011104115481 A CN 2011104115481A CN 201110411548 A CN201110411548 A CN 201110411548A CN 103159661 A CN103159661 A CN 103159661A
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- 0 CCC1(CC1)C(N*)=O Chemical compound CCC1(CC1)C(N*)=O 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N O=C(CCCCl)Cl Chemical compound O=C(CCCCl)Cl CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a preparation method of levetiracetam. The method comprises the steps that: (1) in an inert solvent, an organic alkali is adopted as a catalyst, and (S)-2-amino butanamide hydrochloride and 4-chloroprene chloride are subjected to a reaciton, such that levetiracetam is prepared. The reaction formula (I) is shown below. In the reaction formula (I), the organic alkali is selected from trimethylamine, triethylamine, tripropylamine and diisopropylethylamine ethylamine. Compared with prior arts, the method provided by the invention has the advantages that: according to the invention, the applications of a large amount of inorganic strong alkali and water absorbent are avoided, such that the production of a large amount of strong-alkaline solid waste is avoided; the method has the advantages of short reaction time, easy-to-control operation process, reduced raw material cost, and suitability for large-scale industrial production; with the method, levetiracetam yield is improved, and the obtained levetiracetam has ideal optical purity.
Description
Technical field
The invention belongs to pharmacy field, in particular to a kind of preparation method of antiepileptic drug Levetiracetam.
Background technology
Levetiracetam is a kind of antiepileptic drug of high-efficiency broad spectrum, by the development of Belgian UCB. S.A. (BE) Bruxelles Belgium, at present in EMEA (EMEA) and FDA (FDA) registration, and has been applied to clinical.The Levetiracetam mechanism of action is unique, and curative effect lasting time is long, and untoward reaction is less, and security and better tolerance can be used for add-on, adjuvant drug or the single therapy of broad variety epileptic seizures, and potential applicability in clinical practice is widely arranged.
The chemistry of Levetiracetam is by name: (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide; It is English by name: (S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide; Its molecular formula is: C
8H
14N
2O
2, molecular weight is: 170.21, and structural formula is as shown in the formula shown in (II):
Structural formula (II)
The preparation method of Levetiracetam is existing bibliographical information at present, wherein US Patent No. 4696943 discloses under the condition that adds inorganic strong alkali potassium hydroxide and catalyzer Tetrabutyl amonium bromide, makes (S)-2-amino-butanamide hydrochloride and 4-chlorobutanoylchloride react the preparation Levetiracetam in the inert solvent methylene dichloride.But there is following shortcoming in this technology: 1. use a large amount of inorganic strong alkali potassium hydroxide and water-retaining agent anhydrous sodium sulphate, cause producing a large amount of solid slags, be difficult for realizing industrialization; Potassium hydroxide used need to grind to form fine powder on the other hand, and the industrialization operation easier is large.2. the inventor found through experiments: the very phenomenon of thickness can appear in reaction solution in the process that drips the 4-chlorobutanoylchloride, and operation easier is large.3. product yield is lower, is only 74% left and right.
US Patent No. 4696943 also discloses under the condition that adds the organic bases triethylamine, (S)-2-amino-butanamide hydrochloride and 4-bromo-butyric acid ethyl ester are reacted in toluene, preparation (S)-4-((1-(aminocarboxyl) propyl group) amino) ethyl butyrate, then under existing, the organic bases 2 hydroxy pyrimidine makes (S)-4-((1-(aminocarboxyl) propyl group) amino) ethyl butyrate cyclization, the preparation Levetiracetam is as shown in following reaction formula (III).There is following shortcoming in this technology: 1. two steps of reaction needed complete, and will use more expensive alkaline catalysts 2 hydroxy pyrimidine.2. long reaction time, total recovery is low.
Reaction formula (III)
US Patent No. 7902380 discloses resolution of racemates (R, S) in solvent toluene-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid, obtains (S)-alpha-ethyl-2-oxo-the 1-pyrrolidine acetic acid, and then amidation obtains Levetiracetam.There is following defective in this technology: required reagent is expensive, and the products therefrom total recovery is low.
Summary of the invention
For solving above-mentioned problems of the prior art, the invention provides a kind of preparation method of Levetiracetam.
Particularly, the invention provides:
(1) a kind of preparation method of Levetiracetam, it comprises:
1) in inert solvent, (S)-2-amino-butanamide hydrochloride and 4-chlorobutanoylchloride are reacted, thereby make Levetiracetam, its reaction formula is as shown in following reaction formula (I):
Reaction formula (I)
Wherein, described organic bases is selected from Trimethylamine 99, triethylamine, tripropyl amine or diisopropyl ethyl amine.
(2) method described according to (1), wherein, described organic bases is selected from triethylamine, tripropyl amine or diisopropyl ethyl amine.
(3) method described according to (1), wherein, described inert solvent is selected from benzene,toluene,xylene, methylene dichloride, 1,2-ethylene dichloride or chloroform.
(4) method described according to (3), wherein, described inert solvent is chloroform or methylene dichloride.
(5) method described according to (1), wherein, described inert solvent is 3～20 times of described (S)-2-amino-butanamide hydrochloride in mass.
(6) method described according to (5), wherein, described inert solvent is 8～12 times of described (S)-2-amino-butanamide hydrochloride in mass.
(7) method described according to (1), wherein, the mol ratio of described (S)-2-amino-butanamide hydrochloride, described 4-chlorobutanoylchloride and described organic bases is 1: (1～5): (3～15).
(8) method described according to (7), wherein, the mol ratio of described (S)-2-amino-butanamide hydrochloride, described 4-chlorobutanoylchloride and described organic bases is 1: (1.1～3): (2～6).
(9) method described according to (1), wherein, described temperature of reaction is-15 ℃～15 ℃.
(10) method described according to (9), wherein, described temperature of reaction is-5 ℃～5 ℃.
(11) method described according to (1), wherein, the described reaction times is 2～15 hours.
(12) method described according to (11), wherein, the described reaction times is 3～8 hours.
(13) according to the described method of any one in (1)-(12), wherein, described method also comprises:
2) with step 1) Levetiracetam that makes carries out recrystallization, thereby obtains the Levetiracetam finished product.
Method of the present invention compared with prior art has the following advantages and positively effect:
1. the present invention realizes that (S)-2-amino-butanamide hydrochloride and 4-chlorobutanoylchloride carry out single step reaction and prepare Levetiracetam under the condition that organic alkali exists, compare with the disclosed method of US Patent No. 4696943 (referring to its specification sheets embodiment 4), the present invention avoids using a large amount of inorganic strong alkalis and water-retaining agent, can not produce a large amount of strong basicity solid slags.
2. what the present invention adopted is organic alkali, can make reaction system be in homogeneous phase, thereby avoid using the phase-transfer catalyst Tetrabutyl amonium bromide, and organic bases and inert solvent that the present invention uses is common agents, cheaply is easy to get, and has therefore reduced raw materials cost.
3. short, operating process of reaction times of the present invention is easy to control, and reaction solution the thickness state can not occur, is fit to industrialized production.
4. method of the present invention has improved the yield of Levetiracetam, and the optical purity of the Levetiracetam of gained is desirable.
Embodiment
Below the invention will be further described for the description by embodiment, but this is not to be limitation of the present invention, those skilled in the art are according to basic thought of the present invention, can make various modifications or improvement, but only otherwise break away from basic thought of the present invention, all within the scope of the present invention.
The purpose of this invention is to provide a kind of reaction times short, pollute little, product yield and optical purity high, be suitable for the Levetiracetam preparation method of suitability for industrialized production.
Levetiracetam preparation method provided by the invention comprises: 1) in inert solvent, under suitable organic bases environment, make (S)-2-amino-butanamide hydrochloride and 4-chlorobutanoylchloride directly carry out single step reaction and make Levetiracetam, its reaction formula is as shown in following reaction formula (I):
Reaction formula (I)
Wherein, organic bases of the present invention can be Trimethylamine 99, triethylamine, tripropyl amine or diisopropyl ethyl amine, is preferably tripropyl amine or diisopropyl ethyl amine.The smooth ideal yield coefficient in left second rubbish west that the method according to this invention obtains, optical purity is high.
According to a kind of embodiment of the present invention, inert solvent of the present invention can be inert organic solvents, for example benzene,toluene,xylene, methylene dichloride, 1, and 2-ethylene dichloride, chloroform are preferably chloroform.The consumption of inert solvent can be 3～20 times of (S)-2-amino-butanamide hydrochloride in mass.In the methods of the invention, the too high meeting of the consumption of inert solvent makes speed of response slack-off, and might make reaction not exclusively, and product yield reduces; The consumption of inert solvent is too low, and more side reactions can occur, and reduce product purity.Preferably, the consumption of inert solvent is 8～12 times of (S)-2-amino-butanamide hydrochloride in mass.
According to another embodiment of the present invention, the mol ratio of (S)-2-amino-butanamide hydrochloride of the present invention, 4-chlorobutanoylchloride and preferred organic bases can be 1: (1～5): (3～15).In the methods of the invention, the molar ratio of 4-chlorobutanoylchloride and organic bases is too high can increase raw materials cost; The too low meeting of mol ratio makes reaction not exclusively, causes product yield and purity drop.Preferably, the mol ratio of described (S)-2-amino-butanamide hydrochloride, 4-chlorobutanoylchloride and preferred organic bases is 1: (1.1～3): (2～6).
According to another embodiment of the present invention, temperature of reaction of the present invention can be-15 ℃～15 ℃.In the methods of the invention, the too high meeting of temperature of reaction makes the product racemization, reduces the optical purity of product; The too low meeting of temperature of reaction makes reaction slack-off, and conversion rate of products reduces.Preferably, described temperature of reaction is-5 ℃～5 ℃.
According to another embodiment of the present invention, the reaction times of the present invention can be 2～15 hours.In the methods of the invention, too short meeting of reaction times makes reaction not exclusively, the yield of product and purity drop; The long transformation efficiency that can not improve again product of reaction times can increase production cost on the contrary, even might produce more side reaction.Preferably, the described reaction times is 3～8 hours.
According to another preferred embodiment of the invention, method of the present invention also comprises: 2) with step 1) Levetiracetam that makes carries out recrystallization, thereby obtains the Levetiracetam finished product.
Mode by the following examples further explains and describes content of the present invention, but these embodiment are not to be construed as limiting the scope of the invention.
(S)-2-amino-butanamide hydrochloride in following examples can be available from Fuxin, Liaoning Province auspicious chemical industry of dragon company limited, and the 4-chlorobutanoylchloride can be available from Huzhou, Zhejiang Province chemical industry company limited of salon; High performance liquid chromatograph can be available from Shimadzu company, and model is Nexera UHPLC LC-30A.
The HPLC midpoint controlling method that relates in following examples is:
1. chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica; (get dipotassium hydrogen phosphate 2.0g, add water 1000ml and make dissolving, the phosphoric acid solution with 10% is regulated pH value to 6.0)-acetonitrile (95: 5) is moving phase with phosphate buffered saline buffer; Detect wavelength 205nm; Theoretical plate number should be not less than 3000 by Levetiracetam peak calculating.
2. assay method: get the 2ml reaction solution, add the dilution of 10ml moving phase, as need testing solution.Get 10 μ l need testing solution injection liquid chromatographies, record color atlas, measure the total chromatographic peak area that desolventizes on the area at each peak and color atlas beyond the peak.Calculate by area normalization method the percentage that Levetiracetam principal constituent peak area accounts for the total area.
The measuring method of the liquid chromatography purity of the Levetiracetam that relates in following examples is:
1. chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica; (get dipotassium hydrogen phosphate 2.0g, add water 1000ml and make dissolving, the phosphoric acid solution with 10% is regulated pH value to 6.0)-acetonitrile (95: 5) is moving phase with phosphate buffered saline buffer; Detect wavelength 205nm; Theoretical plate number should be not less than 3000 by Levetiracetam peak calculating.
2. assay method: get Levetiracetam trial-product (self-control Levetiracetam product) appropriate, accurately weighed, add the moving phase dissolving and quantitatively dilution make the solution that contains 1mg in every 1ml, as need testing solution; Precision measures need testing solution 1ml, puts in the 100ml measuring bottle, adds moving phase and is diluted to scale, shakes up, and precision measures 1ml, puts in the 10ml measuring bottle, adds moving phase and is diluted to scale, shakes up, in contrast solution.Precision measures contrast solution 10 μ l, and the injection liquid chromatography is regulated instrumental sensitivity, makes the peak height at principal constituent peak be about the 10%-20% of registering instrument full range; Precision measures contrast solution, each 10 μ l of need testing solution again, difference injection liquid chromatography, and the need testing solution color atlas is recorded to 4 times of main peak retention time.After the deduction solvent peak, with the percentage of the single maximum contaminant of calculated by peak area and total impurities.
3. the method for calculation of the liquid chromatography purity of Levetiracetam are:
Single maximum contaminant (%)=(A
Single maximum contaminant in trial-product/ A
Contrast) * 0.1% total impurities (%)=[(A
The trial-product total peak area-A
Trial-product main peak area)/A
ContrastThe liquid chromatography purity (%) of] * 0.1% Levetiracetam=100%-total impurities (%)
Wherein, A is peak area.
The measuring method of the optical isomer purity that relates in following examples is:
1. chromatographic condition and system suitability: with AD-H post (250 * 4.6mm, 5 μ m); Take normal hexane-dehydrated alcohol (80: 20) as moving phase; Detect wavelength 215nm; Get the Levetiracetam raceme appropriate, add moving phase dissolving and quantitatively dilution make and the solution that does not contain 0.1mg in 1ml, as system suitability solution; Precision measures system suitability solution 20 μ l, and the injection liquid chromatography records color atlas.Peak sequence is Levetiracetam enantiomer, Levetiracetam main peak.
2. assay method: it is appropriate, accurately weighed to get this product, add the moving phase dissolving and quantitatively dilution make the solution that approximately contains 1mg in every 1ml, as need testing solution; Precision measures need testing solution 1ml, puts in the 200ml measuring bottle, adds moving phase and is diluted to scale, shakes up solution in contrast.Precision measures contrast solution 20 μ l, and the injection liquid chromatography is regulated instrumental sensitivity, is the 10%-20% that the principal constituent peak height is about the registering instrument full range; Precision measures need testing solution and each 20 μ l of contrast solution again, and the injection liquid chromatography, record color atlas respectively.If any impurity peaks, impurity peak area must not be greater than contrast solution main peak area in the position of enantiomer for the color atlas of need testing solution.
3. optical isomer purity method of calculation:
Isomer (%)=(A
Trial-product isomer area/ A
The contrast area) * 0.5%
The calculation formula of the yield of the Levetiracetam that relates in following examples is:
The quality (g) * 100% of the molecular weight (g/mol) of the molecular weight (g/mol) * (S) of the quality (g) of the yield of Levetiracetam=reaction gained Levetiracetam/Levetiracetam-2-amino-butanamide hydrochloride/reaction (S)-2-amino-butanamide hydrochloride used
Embodiment 1
with (S)-2-amino-butanamide hydrochloride (69.3 grams, 0.5mol), chloroform (831.6 gram), tripropyl amine (300.7g, 2.1mol), join in three mouthfuls of reaction flasks that low-reading thermometer is housed, stirred 10 minutes, begin cooling evenly, when being down to-5 ℃, begin to drip 4-chlorobutanoylchloride (141g, 1mol), whole dropping process temperature remains between-5～0 ℃, approximately dropwised in 30 minutes, insulation continues reaction 4 hours at 0～5 ℃, in HPLC, the control raw material disappears, product purity is 95.52%, stopped reaction, suction filtration is removed the solid in reaction solution, filtrate (0.09MPa) evaporate to dryness that reduces pressure under 50 ℃ becomes faint yellow solid, add the 600ml ethyl acetate backflow to clarification, naturally cooling, freezing (5 ℃) crystallization is 5 hours again, suction filtration, filter cake is washed till white with glacial acetic acid ethyl ester (5 ℃), 60 ℃ of oven dry, get Levetiracetam 72.25 grams, yield 84.9%, liquid chromatography purity is 99.92%, single maximum contaminant is 0.011%, in liquid chromatography, optical isomer purity is 0.025%.
Embodiment 2
with (S)-2-amino-butanamide hydrochloride (69.3 grams, 0.5mol), chloroform (831.6 gram), diisopropyl ethyl amine (155g, 1.2mol), join in three mouthfuls of reaction flasks that low-reading thermometer is housed, stirred 10 minutes, begin cooling evenly, when being down to-5 ℃, begin to drip 4-chlorobutanoylchloride (211.5g, 1.5mol), whole dropping process temperature remains between-5～5 ℃, approximately dropwised in 30 minutes, insulation continues reaction 4 hours at 0～5 ℃, in HPLC, the control raw material disappears, product purity is 95.26%, stopped reaction, suction filtration is removed the solid in reaction solution, filtrate (0.09MPa) evaporate to dryness that reduces pressure under 50 ℃ becomes faint yellow solid, add the 600ml ethyl acetate backflow to clarification, naturally cooling, freezing (5 ℃) crystallization is 5 hours again, suction filtration, filter cake is washed till white with glacial acetic acid ethyl ester (5 ℃), 60 ℃ of oven dry, get Levetiracetam 71.57 grams, yield 84.1%, liquid chromatography purity is 99.87%, single maximum contaminant is 0.015%, in liquid chromatography, optical isomer purity is 0.028%.
Embodiment 3
with (S)-2-amino-butanamide hydrochloride (69.3 grams, 0.5mol), chloroform (831.6 gram), triethylamine (177.1g, 1.75mol), join in three mouthfuls of reaction flasks that low-reading thermometer is housed, stirred 10 minutes, begin cooling evenly, when being down to-5 ℃, begin to drip 4-chlorobutanoylchloride (141g, 1mol), whole dropping process temperature remains between-5～0 ℃, approximately dropwised in 30 minutes, insulation continues reaction 6 hours at 0～5 ℃, in HPLC, the control raw material disappears, product purity is 93.22%, stopped reaction, suction filtration is removed the solid in reaction solution, filtrate (0.09MPa) evaporate to dryness that reduces pressure under 50 ℃ becomes faint yellow solid, add the 600ml ethyl acetate backflow to clarification, naturally cooling, freezing (5 ℃) crystallization is 5 hours again, suction filtration, filter cake is washed till white with glacial acetic acid ethyl ester (5 ℃), 60 ℃ of oven dry, get Levetiracetam 72.35 grams, yield 85.0%, liquid chromatography purity is 99.79%, single maximum contaminant is 0.024%, in liquid chromatography, optical isomer purity is 0.031%.
Embodiment 4
with (S)-2-amino-butanamide hydrochloride (69.3 grams, 0.5mol), methylene dichloride (623.7 gram), tripropyl amine (300.7g, 2.1mol), join in three mouthfuls of reaction flasks that low-reading thermometer is housed, stirred 10 minutes, begin cooling evenly, when being down to-5 ℃, begin to drip 4-chlorobutanoylchloride (211.5g, 1.5mol), whole dropping process temperature remains between-5～0 ℃, approximately dropwised in 30 minutes, insulation continues reaction 3.5 hours at 0～5 ℃, in HPLC, the control raw material disappears, product purity is 94.81%, stopped reaction, suction filtration is removed the solid in reaction solution, filtrate (0.09MPa) evaporate to dryness that reduces pressure under 50 ℃ becomes faint yellow solid, add the 600ml ethyl acetate backflow to clarification, naturally cooling, freezing (5 ℃) crystallization is 5 hours again, suction filtration, filter cake is washed till white with glacial acetic acid ethyl ester (5 ℃), 60 ℃ of oven dry, get Levetiracetam 70.82 grams, yield 83.2%, liquid chromatography purity is 99.77%, single maximum contaminant is 0.027%, in liquid chromatography, optical isomer purity is 0.029%.
Embodiment 5
with (S)-2-amino-butanamide hydrochloride (69.3 grams, 0.5mol), chloroform (831.6 gram), diisopropyl ethyl amine (387.6g, 3mol), join in three mouthfuls of reaction flasks that low-reading thermometer is housed, stirred 10 minutes, begin cooling evenly, when being down to-5 ℃, begin to drip 4-chlorobutanoylchloride (211.5g, 1.5mol), whole dropping process temperature remains between-5～5 ℃, approximately dropwised in 30 minutes, insulation continues reaction 3 hours at 0～5 ℃, in HPLC, the control raw material disappears, product purity is 96.66%, stopped reaction, suction filtration is removed the solid in reaction solution, filtrate (0.09MPa) evaporate to dryness that reduces pressure under 50 ℃ becomes faint yellow solid, add the 600ml ethyl acetate backflow to clarification, naturally cooling, freezing (5 ℃) crystallization is 5 hours again, suction filtration, filter cake is washed till white with glacial acetic acid ethyl ester (5 ℃), 60 ℃ of oven dry, get Levetiracetam 73.52 grams, yield 86.4%, liquid chromatography purity is 99.69%, single maximum contaminant is 0.021%, in liquid chromatography, optical isomer purity is 0.021%.
Embodiment 6
with (S)-2-amino-butanamide hydrochloride (69.3 grams, 0.5mol), chloroform (831.6 gram), triethylamine (101.2g, 1.0mol), join in three mouthfuls of reaction flasks that low-reading thermometer is housed, stirred 10 minutes, begin cooling evenly, when being down to-5 ℃, begin to drip 4-chlorobutanoylchloride (77.6g, 0.55mol), whole dropping process temperature remains between-5～0 ℃, approximately dropwised in 30 minutes, insulation continues reaction 8 hours at 0～5 ℃, in HPLC, the control raw material disappears, product purity is 92.32%, stopped reaction, suction filtration is removed the solid in reaction solution, filtrate (0.09MPa) evaporate to dryness that reduces pressure under 50 ℃ becomes faint yellow solid, add the 600ml ethyl acetate backflow to clarification, naturally cooling, freezing (5 ℃) crystallization is 5 hours again, suction filtration, filter cake is washed till white with glacial acetic acid ethyl ester (5 ℃), 60 ℃ of oven dry, get Levetiracetam 69.15 grams, yield 81.3%, liquid chromatography purity is 99.88%, single maximum contaminant is 0.009%, in liquid chromatography, optical isomer purity is 0.010%.
Embodiment 7
with (S)-2-amino-butanamide hydrochloride (69.3 grams, 0.5mol), chloroform (831.6 gram), Trimethylamine 99 (124.1g, 2.1mol), join in three mouthfuls of reaction flasks that low-reading thermometer is housed, stirred 10 minutes, begin cooling evenly, when being down to-5 ℃, begin to drip 4-chlorobutanoylchloride (141g, 1mol), whole dropping process temperature remains between-5～0 ℃, approximately dropwised in 30 minutes, insulation continues reaction 6 hours at 0～5 ℃, in HPLC, the control raw material disappears, product purity is 93.37%, stopped reaction, suction filtration is removed the solid in reaction solution, filtrate (0.09MPa) evaporate to dryness that reduces pressure under 50 ℃ becomes faint yellow solid, add the 600ml ethyl acetate backflow to clarification, naturally cooling, freezing (5 ℃) crystallization is 5 hours again, suction filtration, filter cake is washed till white with glacial acetic acid ethyl ester (5 ℃), 60 ℃ of oven dry, get Levetiracetam 59.12 grams, yield 69.5%, liquid chromatography purity is 99.68%, single maximum contaminant is 0.017%, in liquid chromatography, optical isomer purity is 0.033%.
Embodiment 8
with (S)-2-amino-butanamide hydrochloride (69.3 grams, 0.5mol), chloroform (1039.5 gram), tripropyl amine (300.7g, 2.1mol), join in three mouthfuls of reaction flasks that low-reading thermometer is housed, stirred 10 minutes, begin cooling evenly, when being down to-5 ℃, begin to drip 4-chlorobutanoylchloride (141g, 1mol), whole dropping process temperature remains between-5～0 ℃, approximately dropwised in 30 minutes, insulation continues reaction 10 hours at 0～5 ℃, in HPLC, the control raw material disappears, product purity is 91.52%, stopped reaction, suction filtration is removed the solid in reaction solution, filtrate (0.09MPa) evaporate to dryness that reduces pressure under 50 ℃ becomes faint yellow solid, add the 600ml ethyl acetate backflow to clarification, naturally cooling, freezing (5 ℃) crystallization is 5 hours again, suction filtration, filter cake is washed till white with glacial acetic acid ethyl ester (5 ℃), 60 ℃ of oven dry, get Levetiracetam 57.09 grams, yield 67.1%, liquid chromatography purity is 99.89%, single maximum contaminant is 0.031%, in liquid chromatography, optical isomer purity is 0.016%.
Embodiment 9
with (S)-2-amino-butanamide hydrochloride (69.3 grams, 0.5mol), methylene dichloride (1039.5 gram), tripropyl amine (300.7g, 2.1mol), join in three mouthfuls of reaction flasks that low-reading thermometer is housed, stirred 10 minutes, begin cooling evenly, when being down to-5 ℃, begin to drip 4-chlorobutanoylchloride (141g, 1mol), whole dropping process temperature remains between-5～0 ℃, approximately dropwised in 30 minutes, insulation continues reaction 10 hours at 0～5 ℃, in HPLC, the control raw material disappears, product purity is 92.31%, stopped reaction, suction filtration is removed the solid in reaction solution, filtrate (0.09MPa) evaporate to dryness that reduces pressure under 50 ℃ becomes faint yellow solid, add the 600ml ethyl acetate backflow to clarification, naturally cooling, freezing (5 ℃) crystallization is 5 hours again, suction filtration, filter cake is washed till white with glacial acetic acid ethyl ester (5 ℃), 60 ℃ of oven dry, get Levetiracetam 59.15 grams, yield 69.5%, liquid chromatography purity is 99.58%, single maximum contaminant is 0.042%, in liquid chromatography, optical isomer purity is 0.019%.
Embodiment 10
with (S)-2-amino-butanamide hydrochloride (69.3 grams, 0.5mol), chloroform (1386 gram), tripropyl amine (300.7g, 2.1mol), join in three mouthfuls of reaction flasks that low-reading thermometer is housed, stirred 10 minutes, begin cooling evenly, when being down to-5 ℃, begin to drip 4-chlorobutanoylchloride (141g, 1mol), whole dropping process temperature remains between-5～0 ℃, approximately dropwised in 30 minutes, insulation continues reaction 15 hours at 0～5 ℃, in HPLC, the control raw material disappears, product purity is 89.57%, stopped reaction, suction filtration is removed the solid in reaction solution, filtrate (0.09MPa) evaporate to dryness that reduces pressure under 50 ℃ becomes faint yellow solid, add the 600ml ethyl acetate backflow to clarification, naturally cooling, freezing (5 ℃) crystallization is 5 hours again, suction filtration, filter cake is washed till white with glacial acetic acid ethyl ester (5 ℃), 60 ℃ of oven dry, get Levetiracetam 50.19 grams, yield 59.0%, liquid chromatography purity is 99.81%, single maximum contaminant is 0.041%, in liquid chromatography, optical isomer purity is 0.012%.
Claims (13)
1. the preparation method of a Levetiracetam, it comprises:
1) in inert solvent, (S)-2-amino-butanamide hydrochloride and 4-chlorobutanoylchloride are reacted, thereby make Levetiracetam, its reaction formula is as shown in following reaction formula (I):
Reaction formula (I)
Wherein, described organic bases is selected from Trimethylamine 99, triethylamine, tripropyl amine or diisopropyl ethyl amine.
2. method according to claim 1, wherein, described organic bases is selected from triethylamine, tripropyl amine or diisopropyl ethyl amine.
3. method according to claim 1, wherein, described inert solvent is selected from benzene,toluene,xylene, methylene dichloride, 1,2-ethylene dichloride or chloroform.
4. method according to claim 3, wherein, described inert solvent is chloroform or methylene dichloride.
5. method according to claim 1, wherein, described inert solvent is 3～20 times of described (S)-2-amino-butanamide hydrochloride in mass.
6. method according to claim 5, wherein, described inert solvent is 8～12 times of described (S)-2-amino-butanamide hydrochloride in mass.
7. method according to claim 1, wherein, the mol ratio of described (S)-2-amino-butanamide hydrochloride, described 4-chlorobutanoylchloride and described organic bases is 1: (1～5): (3～15).
8. method according to claim 7, wherein, the mol ratio of described (S)-2-amino-butanamide hydrochloride, described 4-chlorobutanoylchloride and described organic bases is 1: (1.1～3): (2～6).
9. method according to claim 1, wherein, described temperature of reaction is-15 ℃～15 ℃.
10. method according to claim 9, wherein, described temperature of reaction is-5 ℃～5 ℃.
11. method according to claim 1, wherein, the described reaction times is 2～15 hours.
12. method according to claim 11, wherein, the described reaction times is 3～8 hours.
13. the described method of any one according to claim 1-12, wherein, described method also comprises:
2) with step 1) Levetiracetam that makes carries out recrystallization, thereby obtains the Levetiracetam finished product.
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