CN1288133C - Synthesis of (S)-alpha-ethyl-2-oxi-1-pentazane acetamide - Google Patents
Synthesis of (S)-alpha-ethyl-2-oxi-1-pentazane acetamide Download PDFInfo
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Abstract
The present invention discloses a new technology for synthesizing antiepileptic medicine (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide (levetiracetam), which comprises: n-propanal and sodium cyanide are used as initial raw materials; after four-step reaction of Straker, hydrolyzation, resolution and cyclization, the levetiracetam is prepared. In the method, a diastereoisomer resolution method is adopted; under the alkaline condition of organic solvent, (S)-a-aminobutanamide hydrochloride(IV) and (R)-a-aminobutanamide hydrochloride(IV) are respectively prepared. The synthetic route of the present invention is shortened to four steps from six steps in the literature, and the yield is increased to 10% from 4.7%. The new synthetic technology of the present invention has the advantages of simple and convenient operation, high yield and low cost, and is suitable for large-scale industrialized production.
Description
Technical field
The present invention relates to the preparation method of antiepileptic drug, the synthesis technique of particularly (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide (Levetiracetam).
Background technology
Antiepileptic drug is prevention and a class medicine for the treatment of the paroxysmal that is caused by the epileptics outbreak, the imbalance of temporary brain function.Levetiracetam (Levetiracetam) is the antiepileptic drug of being developed by Belgian UCB. S.A. (BE) Bruxelles Belgium; compare with existing antiepileptic drug; this product does not show the effect of inhibition and excitor nerve transmission; in addition, this product can the selective protection limitation and former generalized epilepsy and do not influence the internal metabolism of other antiepileptic drugs.
Preparation method about Levetiracetam once had report EP0165919B1 and CN1015541B to introduce the synthetic route of (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide (Levetiracetam) respectively in the literature, mainly contain two, the one, be starting raw material with positive propionic aldehyde, prepare target compound through Strake reaction, hydrolysis, fractionation, esterification, acid amides, cyclization six-step process; The 2nd, be starting raw material with the butanic acid, be total to six-step process through bromination, esterification, N-hydrocarbonylation, hydrolysis, fractionation, amidation and prepare target compound.Article one, the advantage of synthetic route is that raw material type is less, low price, cost be low; Shortcoming be yield on the low side be 4.7% only, reactions steps is long, reaction is too complicated, is not suitable for suitability for industrialized production.Second synthetic route document total recovery is 8.7%, and former steps of this method are classical reaction, but the raw materials cost of being adopted is higher than first method, needs some corrosion resistant conversion units, severe reaction conditions in the operation simultaneously.
Summary of the invention
Synthesis technique of the present invention is that the inventive process of carrying out on the basis of former document is improved.The method that present method adopts non-corresponding isomer to split first, will (±)-a-amino-butanamide hydrochloride through split obtain respectively optically pure (S)-a-amino-butanamide hydrochloride with (R)-the a-amino-butanamide hydrochloride.Obviously having simplified in the former document with the a-aminobutyric acid is the method for starting raw material through fractionation, esterification, amidation three-step reaction preparation (S) optics intermediate.Prepared optics intermediate (the S)-a-amino-butanamide hydrochloride of the present invention simultaneously can obtain optically pure (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide by ring-closure reaction, and physico-chemical properties such as its optical value, fusing point are consistent with former document.
Technical scheme of the present invention is as follows:
A kind of is the synthesis technique of starting raw material through following reaction formula prepared in reaction (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide with positive propionic aldehyde, sodium cyanide:
It is characterized in that: in resolution reaction, be raw material, under the alkaline condition of organic solvent, adopt the diastereomer method for splitting, obtain optically pure (S)-a-amino-butanamide hydrochloride (IV) respectively with DL a-amino-butanamide hydrochloride (III); (R)-a-amino-butanamide hydrochloride (IV ').
Fractionation organic solvent of the present invention is C
1-C
4Lower alcohol or their mixed solvent.
Fractionation alkalization solvent of the present invention is sodium hydroxide, ammoniacal liquor, triethylamine or potassium hydroxide.
The used resolving agent of diastereomer Split Method of the present invention is L-+-tartrate, (+) or (-)-amygdalic acid, (+) or (-) oxysuccinic acid, (+) or (-) lactic acid.
The used solvent of fractionation gained crude product recrystallization of the present invention is C
1-C
4Lower alcohol or 50%-98% alcohol-water mixture.
C of the present invention
1-C
4Lower alcohol be methyl alcohol, ethanol, Virahol, propyl carbinol.
General method for splitting is induced several different methods such as Split Method, the fractionation of formation diastereomeric salt, formed not enantiomer about what adopt by DL compound and optical resolution agent, foundation is in the difference of the solubleness of solvent, the method of separating, purifying, can be with reference to the method for some documents, as: partly measure Split Method, Split Method etc. mutually.Determine that through a large amount of experiments the present invention adopts the diastereomer method for splitting, its selected resolving agent comprises L-+-tartrate, (+) or (-) amygdalic acid, (+) or (-) oxysuccinic acid, (+) or (-) lactic acid.Particularly preferably be (+)-amygdalic acid, (+)-tartrate, (+)-oxysuccinic acid; Alkalizing agent is sodium hydroxide, ammoniacal liquor, triethylamine or potassium hydroxide; The organic solvent that splits is C
1-C
4Lower alcohol such as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol or their mixed solvent; Best fractionation organic solvent is methyl alcohol or ethanol or methyl alcohol-isopropyl alcohol mixed solvent; Gained oily matter salify in acidic organic solvent can be hydrochloric acid-ethanol, hydrochloric acid-ether or hydrochloric acid-Virahol, preferred especially hydrochloric acid-Virahol; Gained splits the crude product recrystallization can use methyl alcohol, ethanol, Virahol, water, water-ethanol mixed solvent; Particularly preferred solvent is the ethanol-water solution of ethanol, 70-95%, for the salt that splits, separate, can select ion exchange resin, polymeric adsorbent or utilize the physico-chemical property of sodium salt in solvent, separate, free alkali of the present invention is a water-soluble substances, for his separation, can separate according to the character of various sodium salts in solvent.(S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide (Levetiracetam) that adopts the preparation of diastereomer method for splitting is specifically seen description of drawings through infrared, mass spectrum, monocrystalline X-ray diffraction conclusive evidence structure are entirely true.
Be the synthetic route of the present invention (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide (V) below; Wherein reaction formula one is that to be raw material with DL a-amino-butanamide hydrochloride (III) obtain optically pure (S)-a-amino-butanamide hydrochloride (IV) respectively after diastereomer splits; (R)-a-amino-butanamide hydrochloride (IV ').Reaction formula two is synthetic routes of synthetic (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide (V).
Reaction formula one
Reaction formula two
The invention has the advantages that: the method that (1) utilizes chemistry to split, by DL-the a-amino-butanamide prepares optically pure (S)-a-amino-butanamide hydrochloride and (R)-a-amino-butanamide hydrochloride and obviously simplifies building-up reactions step (having the six-step process of former document to shorten to four-step reaction).(2) significantly improved the yield of building-up reactions, brought up to 10% by 4.7% of former document yield.(3) adopt NaCN to substitute the HCN gas of document, simplified the operational hazards degree, avoided atmospheric pollution.(4) simplify technological operation, be more suitable for large-scale industrial production.
Description of drawings:
Fig. 1 is the Levetiracetam infrared spectrogram
Fig. 2 is the Levetiracetam mass spectrum
Fig. 3 is monocrystalline X-ray diffraction Levetiracetam molecular structure solid (front) figure
Specific embodiment
The present invention is further illustrated below in conjunction with embodiment, but do not limit the present invention.
Synthetic (II) of embodiment 1. alpha-amino groups-butyronitrile
In the 2L three-necked bottle, add 63.7g (1.3mol) sodium cyanide, the ammoniacal liquor of 400ml20%, and then add 78.7g (1.47mol) ammonium chloride, stir dissolving down.The positive propionic aldehyde solution of Dropwise 5 8g (1mol), stirred overnight at room temperature is extracted three times with methylene dichloride 200ml.Merge organic extracting solution, add molecular sieve drying.Concentrating under reduced pressure gets the about 60g of crude product alpha-amino group-butyronitrile, is yellow oily liquid.The copperas solution that adds heat in the aqueous solution stirs and removes excessive cryanide ion, and washes containers such as exhausted reaction flask, beaker with copperas solution, merges waste water solution at last and pours in the useless bucket.
Synthetic (II) of embodiment 2. alpha-amino groups-butyronitrile
In the 5L there-necked flask, add sodium cyanide 320g (6.2mol), ammonium chloride 402g (7.4mol), ammoniacal liquor 2500ml, after the solid dissolving was treated in stirring, room temperature dripped propionic aldehyde 290g (5mol), stirs 5 hours, divide four extractions with methylene dichloride (2000ml), the merging organic layer, solvent is to the greatest extent steamed in dry back, gets light yellow oil 416g.
The preparation of embodiment 3. alpha-amino groups-butanamide hydrochloride (III)
The preparation of embodiment 4. alpha-amino groups-butanamide hydrochloride (III)
With the oily matter 416g (4.95mol) that embodiment 2 obtains, in the saturated hydrochloric acid Virahol of dropping 2980ml, stirred overnight at room temperature slowly is warming up to backflow under ice bath, refluxes and stirs 1 hour, and cooling is filtered, and gets crude product 643g.Crude product is added in the round-bottomed bottle of 5L, adds the ethanol (95%) of 3860ml, reflux, cool off, filter product 333g, mp220 ℃, yield 40.2%.(the first step, two step joint account yields)
The preparation (IV) of embodiment 5 (S)-(+)-alpha-amino group-butanamide hydrochloride
In the 5L triangular flask, add the alpha-amino group butanamide hydrochloride of 300g (2.17mol) DL, add 1.8L methyl alcohol 471.6g (4.66mol) triethylamine, jolting is molten-(1) extremely entirely; In another 3L bottle, add 360g (2.37mol), (+) amygdalic acid, 1.6L methyl alcohol stirs molten entirely-(2).(2) are slowly added in (1), and the cold crystallization of separating out is gradually put in jolting.Filter, get crude product 219g, mp135-140 ℃.Crude product is added 80% ethanol 1500ml, and reflux is put cold analysis and is gone out crystallization to molten entirely, filter elaboration (S)-(+)-alpha-amino group-butyramide (+) mandelate 206g, mp140-145 ℃.Elaboration is added in the there-necked flask, adding methyl alcohol, sodium hydroxide 95g (2.39mol), reflux stirred 0.5 hour, and cooling is filtered, and it is inferior to give a baby a bath on the third day after its birth with methyl alcohol, concentrates, and gets yellow oil.Yellow oil is added drop-wise in the 295g hydrogenchloride Virahol (30%), stirs, get white crystals, cooling is filtered, and it is inferior to give a baby a bath on the third day after its birth with Virahol, gets (S)-(+)-alpha-amino group butanamide hydrochloride 103g (IV), and fusing point 260-262 ℃, content 99.65%[α]
D 25+ 27.4 ° (c=1, methyl alcohol), yield 34.5%
The preparation (IV) of embodiment 6 (S)-(+)-alpha-amino group-butanamide hydrochloride
Solution 1: in bottle, add the alpha-amino group butanamide hydrochloride of 119.5g (0.863mol) DL, add 300ml ethanol, 48g (1.2mol) sodium hydroxide, jolting is to molten entirely; Solution 2: in bottle, add 177.6g (1.18mol) L-(+) tartrate, 400ml ethanol stirs molten entirely.Solution 2 is slowly added in the solution 1, and the cold crystallization of separating out is gradually put in jolting.Filter, get crude product 105g, mp145-150 ℃.Crude product is added 70% ethanol 700ml, and reflux is to molten entirely, put cold, to 4 ℃, filter elaboration (S)-(+)-alpha-amino group-butyramide (+) tartrate 101.5g, mp155-160 ℃.The 101.5g elaboration is added in the there-necked flask, adding methyl alcohol, sodium hydroxide 38g (0.949mol), reflux stirred 0.5 hour, and cooling is filtered, and it is inferior to give a baby a bath on the third day after its birth with methyl alcohol, concentrates, and gets yellow oil.Yellow oil is added drop-wise in the 500g hydrogenchloride Virahol (30%), stirs, get white crystals, cooling, filtration is given a baby a bath on the third day after its birth inferior with Virahol, get (S)-(+)-alpha-amino group butanamide hydrochloride 41.9g (IV), and fusing point 260-262 ℃, content 99.3%, [α]
D 25+ 25.7 ° (c=1, methyl alcohol), yield 35.1%.
The preparation (IV) of embodiment 7 (S)-(+)-alpha-amino group-butanamide hydrochloride
The alpha-amino group butanamide hydrochloride of charging capacity: 150g (1.083mol) DL; Potassium hydroxide 127g (2.27mol); Methyl alcohol 800ml-200ml Virahol; (+) oxysuccinic acid 159.6g (1.19mol).Operation gets crude product 105g with embodiment 5, gets mp155-160 ℃ of elaboration 101 gram, yield 37.2% with 95% ethanol 7300ml reflux, elaboration is free through alkali, and hydrochloric acid Virahol salify gets (S)-(+)-alpha-amino group butanamide hydrochloride 30g (IV), fusing point 260-262 ℃, content 99.18%, [α]
D 25+ 34.7 ° (c=1, methyl alcohol), yield 32.2%.
The preparation (IV) of embodiment 8 (S)-(+)-alpha-amino group-butanamide hydrochloride
The alpha-amino group butanamide hydrochloride of charging capacity: 300g (2.166mol) DL; Triethylamine 646ml (4.66mol), methyl alcohol 3400ml, L-(+) tartrate 360g (2.4mol), operation gets crude product 219g with embodiment 5, gets mp158-160 ℃ of elaboration 194.5 gram, yield 35.6% with 75% ethanol 1400ml reflux, elaboration is free through alkali, hydrochloric acid Virahol salify gets (S)-(+)-alpha-amino group butanamide hydrochloride 100g (IV), fusing point 260-262 ℃, content 99.11%[α]
D 25+ 25.4 ° (c=1, methyl alcohol), yield 34.5%
The preparation (IV) of embodiment 9 (S)-(+)-alpha-amino group-butanamide hydrochloride
The alpha-amino group butanamide hydrochloride of charging capacity: 100g (0.722mol) DL; Sodium hydroxide 60g (1.5mol) methyl alcohol 800ml, (+) amygdalic acid 120g (0.789mol), operation gets crude product 72.5g with embodiment 5, get mp140-145 ℃ of elaboration 64.5 gram with 90% ethanol 800ml reflux, elaboration is free through alkali, and hydrochloric acid Virahol salify gets (S)-(+)-alpha-amino group butanamide hydrochloride 28g (IV), fusing point 260-262 ℃, content 99.35%, [α]
D 25+ 33.6 ° (c=1, methyl alcohol), yield 31.8%.
The preparation (IV ') of embodiment 10 (R)-(-)-alpha-amino group-butanamide hydrochloride
The mother liquor that (embodiment 5) is leached crude product (S)-(+)-alpha-amino group-butyramide (+) tartrate is concentrated into the solvent of half, cooling, filter, concentrated solvent is to doing then, free (R)-(-)-alpha-amino group-butyramide (+) tartrate directly made (R)-(-)-alpha-amino group butanamide hydrochloride 35.8g of optical purity, mp260-262 ℃ at last by this free alkali, content 99.1%, [α]
D 25-25.4 ° (c=1, methyl alcohol), yield 30%.
The preparation (IV ') of embodiment 11 (R)-(-)-alpha-amino group-butanamide hydrochloride
Operation just changes embodiment 6 into (embodiment 5) with embodiment 10, (R)-(-)-the alpha-amino group butanamide hydrochloride must measure 89g, and mp260-2 ℃, content 99.45%, [α]
D 25-27.4 ° (c=1, methyl alcohol), yield 35%.
The preparation (IV ') of embodiment 12 (R)-(-)-alpha-amino group-butanamide hydrochloride
Operation just changes embodiment 7 into (embodiment 5) with embodiment 10, (R)-(-)-the alpha-amino group butanamide hydrochloride must measure 28g, and mp260-262 ℃, content 99.5%, [α]
D 25-34.2 ° (c=1, methyl alcohol), yield 23.5%.
The preparation (IV ') of embodiment 13 (R)-(-)-alpha-amino group-butanamide hydrochloride
The mother liquor that (embodiment 8) is leached crude product (S)-(+)-alpha-amino group-butyramide (+) tartrate is concentrated into the solvent of half, cooling, filter, concentrated solvent is to doing then, free (R)-(-)-alpha-amino group-butyramide (+) tartrate directly made (R)-(-)-alpha-amino group butanamide hydrochloride 37.2g of optical purity, mp260-262 ℃ at last by this free alkali, content 98.9%, [α]
D 25-25.4 ° (c=1, methyl alcohol), yield 31.2%.
The preparation (IV ') of embodiment 14 (R)-(-)-alpha-amino group-butanamide hydrochloride
Operation just changes embodiment 9 into (embodiment 5) with embodiment 10, (R)-(-)-the alpha-amino group butanamide hydrochloride must measure 30g, and mp260-262 ℃, content 99.15%, [α]
D 25-27.4 ° (c=1, methyl alcohol), yield 25.14%.
Embodiment 15. (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide (V)
(S)-2-amino-butanamide hydrochloride (IV) 119.5g (0.863mol) is joined in the three-necked bottle, add the 300ml methylene dichloride, add part potassium hydroxide 40g (0.714mol), benzyl triethylamine ammonium chloride 10g (0.576mol), anhydrous sodium sulphate 138g (0.972mol) stirred 10 minutes.Ice bath drips 4-chloro-butyryl chloride 131g (0.929mol) and methylene dichloride 200ml solution down, and temperature is controlled at 10-15 ℃, and about 0.5 hour, stirring at room reaction 5 hours.Add remaining 160g (2.857mol) potassium hydroxide again, react after 7 hours, filter, filtrate concentrates, and adds ethyl acetate, heat moltenly entirely, filters, concentrated crude product 158g.To add ethyl acetate in the crude product, heating for dissolving is filtered, cool off (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide 122.4g, mp117 ℃, content 99.8%[α]
D 25-90.3 ° (C=1, acetone), yield 72%.
Embodiment 16. (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide (V)
(S)-2-amino-butanamide hydrochloride (IV) of 160g (1.55mol) is joined in the three-necked bottle, add the 2L methylene dichloride, add part potassium hydroxide 240g (6mol), benzyl triethylamine ammonium chloride 14g (0.062mol), anhydrous sodium sulphate 192g (1.35mol) stirred 10 minutes.Ice bath drips 4-chloro-butyryl chloride 172g (1.22mol) and methylene dichloride 400ml solution down, and temperature is controlled at 10-15 ℃, and about 0.5 hour, stirring at room reaction 5 hours.Add remaining 80g (2mol) potassium hydroxide again, react after 7 hours, filter, filtrate concentrates, and adds ethyl acetate, heat moltenly entirely, filters, concentrated crude product 160g.To add ethyl acetate in the crude product, heating for dissolving is filtered, cool off (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide 137g, mp117 ℃, content 99.8%[α]
D 25-91.16 ° (C=1, acetone), yield 69.4%.
Claims (6)
1, a kind of is the synthesis technique of starting raw material through following reaction formula prepared in reaction (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide with positive propionic aldehyde, sodium cyanide:
It is characterized in that: in resolution reaction, be raw material, under the alkaline condition of organic solvent, adopt the diastereomer method for splitting, obtain optically pure (S)-alpha-amino group butanamide hydrochloride (IV) respectively with DL alpha-amino group butanamide hydrochloride (III); (R)-alpha-amino group butanamide hydrochloride (IV).
2, synthesis technique according to claim 1 is characterized in that the organic solvent that splits is C
1-C
4Alcohol or their mixed solvent.
3, synthesis technique according to claim 1 is characterized in that the alkalization solvent that splits is sodium hydroxide, ammoniacal liquor, triethylamine or potassium hydroxide.
4, synthesis technique according to claim 1 is characterized in that the used resolving agent of diastereomer Split Method is L-+-tartrate, (+) or (-)-amygdalic acid, (+) or (-) oxysuccinic acid, (+) or (-) lactic acid.
5, synthesis technique according to claim 1, it is characterized in that splitting the used solvent of gained crude product recrystallization is C
1-C
4Alcohol or 50%-98% alcohol-water mixture.
6, according to claim 2 or 5 described synthesis techniques, it is characterized in that described C
1-C
4Alcohol be methyl alcohol, ethanol, Virahol or propyl carbinol.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101130504B (en) * | 2006-08-25 | 2010-07-28 | 苏州雅本化学股份有限公司 | Synthesis, split and racemization method for preparing chirality medicament levetiracetam midbody (S)-(+)-2-amido butyramide hydrochlorate |
| CN102471236A (en) * | 2009-07-22 | 2012-05-23 | 日本凡凯姆股份有限公司 | Process for producing inorganic acid salt of 2-aminobutylamide |
| CN101811978B (en) * | 2010-04-12 | 2013-01-23 | 华东师范大学 | Preparation method of 2-aminobutanamide hydrochloride |
| CN101928229A (en) * | 2010-07-01 | 2010-12-29 | 黄冈华阳药业有限公司 | Process method for producing L-2-aminobutanamide hydrochloride serving as intermediate of levetiracetam |
| CN102584622B (en) * | 2012-02-15 | 2013-08-14 | 雅本化学股份有限公司 | Preparation method of L-2-aminobutanamide hydrochloride |
| CN103012190B (en) * | 2012-12-05 | 2015-03-18 | 江苏拜克新材料有限公司 | Synthesis method of S-2-aminobutanamide hydrochloride |
| CN103304464B (en) * | 2013-05-10 | 2014-06-11 | 成都合迅医药技术有限公司 | Preparation method of levetiracetam |
| CN103626672B (en) * | 2013-11-12 | 2014-09-24 | 河北序能生物技术有限公司 | Method for preparing (S)-2-aminobutanamide hydrochloride |
| CN104860863B (en) * | 2015-04-10 | 2017-06-20 | 惠州信立泰药业有限公司 | Levetiracetam and the pharmaceutical composition containing it |
| CN112300027B (en) * | 2020-09-27 | 2023-04-25 | 安徽泰格生物科技有限公司 | Preparation method of amino butyronitrile |
| CN113582903B (en) * | 2021-08-25 | 2023-06-06 | 沧州那瑞化学科技有限公司 | Method for synthesizing medicine for treating epilepsy by using L-2-aminobutanamide hydrochloride |
| CN115403500A (en) * | 2022-10-08 | 2022-11-29 | 上海壮铭生物医药有限公司 | Preparation method of levetiracetam |
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