CN102382027B - Method for preparing levetiracetam - Google Patents
Method for preparing levetiracetam Download PDFInfo
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- CN102382027B CN102382027B CN2011102803612A CN201110280361A CN102382027B CN 102382027 B CN102382027 B CN 102382027B CN 2011102803612 A CN2011102803612 A CN 2011102803612A CN 201110280361 A CN201110280361 A CN 201110280361A CN 102382027 B CN102382027 B CN 102382027B
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- butanamide
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Abstract
The invention provides a method for preparing levetiracetam, comprising the following steps of: taking 2-bromine butyric acid as a raw material, subjecting to ammonolysis reaction, concentrating till drying, adding carbinol, crystallizing and drying so as to obtain 2-amino butyramide solid; dissolving the 2-amino butyramide solid in the carbinol, resolving and salifying by utilizing L-(+) - tartaric acid under the existence of a catalyst so as to obtain S-(+)-2- amino butyramide tartrate; and putting the S-(+)-2- amino butyramide tartrate into an aprotic solvent, adding anhydrous sodium sulfate and tetrabutyl amonium bromide, reacting with 4-chlorobutyryl chloride under an alkaline condition, filtering, decompressing filtrate, recovering the aprotic solvent, adding acetone into the surplus filtrate, recrystallizing and drying so as to obtain levetiracetam solid. The preparation method provided by the invention has the advantages of short reaction step, mild reaction condition, low cost and high yield.
Description
Technical field
The present invention relates to a kind of preparation method of medicine, relate in particular to a kind of preparation method of Levetiracetam.
Background technology
Antiepileptic drug is prevention and a class medicine for the treatment of the paroxysmal that has the epileptics outbreak to cause, the imbalance of temporary brain function.Levetiracetam (Levetiracetam) is the unique pharmacological action that is used for the treatment of limitation and secondary generalized epilepsy that has Belgian UCB. S.A. (BE) Bruxelles Belgium to develop, and does not affect other antiepileptic drug internal metabolism.
The synthetic route of Levetiracetam roughly can be divided into following two:
Article one, be take 2-Pyrrolidone and 2-bromo-butyric acid methyl esters etc. as raw material, obtain the route of Levetiracetam through N-hydrocarbylation, hydrolysis, fractionation, amidation.This route steps is simple, but reaction conditions requires need to use the hazardous substance of severe toxicity under harshness or mild conditions.
The second route is through (S)-2-amino-butanamide; Or, take the 2-bromo-butyric acid as raw material, through ammonification, esterification, ammonia solution, fractionation, obtain (S)-2-amino-butanamide.Intermediate (S)-2-amino-butanamide is converted into the method for Levetiracetam again with 4-chlorobutanoylchloride or the amidation of 4-neoprene acid ethyl ester, cyclization.This route traditional technology raw material is cheaply easily purchased, but that shortcoming is step is long, yield is low, technique is too complicated.
Summary of the invention
Purpose of the present invention is intended to overcome the shortcoming that exists in above-mentioned prior art, and the method for the highly purified Levetiracetam of preparation that a kind of reactions steps is short, reaction conditions is gentle, cost is low, yield is high is provided.The present invention realizes by following technical proposals:
A kind of preparation method of Levetiracetam, comprise the steps:
(1) take the 2-bromo-butyric acid as raw material, be concentrated into driedly after ammonolysis reaction, add methanol crystallization, oven dry, make 2-amino-butanamide solid;
(2) with 2-amino-butanamide dissolution of solid in methyl alcohol,, take salicylic aldehyde as catalyzer, split salify through L-(+)-tartrate and make S-(+)-2-amino-butanamide tartrate;
(3) S-(+)-2-amino-butanamide tartrate drops in aprotic solvent, add anhydrous sodium sulphate, Tetrabutyl amonium bromide, under alkaline condition, with filtration after the reaction of 4-chlorobutanoylchloride, after filtrate decompression has been reclaimed aprotic solvent, add acetone recrystallization in residual filtrate, dry to obtain the Levetiracetam solid.
Further,
Raw material 2-bromo-butyric acid in described step (1) is 1 mole, and the ammonia in ammonolysis reaction is ammoniacal liquor or liquefied ammonia more than 5 moles; The temperature of ammonolysis reaction is-5 ℃～0 ℃; Reaction times is 3～5 days.
L-(+) in described step (2)-tartrate is 0.5～1.5 mole, and salicylic aldehyde is 0.01～0.5 mole.
Catalyzer in described step (2) can also be the phenyl aldehyde of 0.01～0.5 mole.
Alkali in described step (3) is potassium hydroxide or the sodium hydroxide more than 4 moles; Described aprotic solvent is a kind of in methylene dichloride, dimethyl tertbutyl ether or acetonitrile; Described temperature of reaction is-5 ℃～0 ℃, reacts complete rear insulation 5 hours.
Reaction equation of the present invention is as follows:
The present invention compared with prior art, possesses following outstanding substantive distinguishing features and significant progressive:
(1) prepare in 2-amino-butanamide process at the 2-bromo-butyric acid, traditional technology need to be passed through ammonification, esterification, ammonia solution, and the present invention only need pass through ammonification, thereby reactions steps of the present invention is short.
(2) prepare in 2-amino-butanamide process at the 2-bromo-butyric acid, desired reaction temperature is-5 ℃～0 ℃, and without the requirement of special low temperature and high temperature, thereby reaction conditions of the present invention is gentle.
(3) in 2-amino-butanamide preparation (S)-2-amino-butanamide tartrate process, with L-(+)-tartrate, split, resolution yield is high., because the 2-bromo-butyric acid, through the 2-amino-butanamide of ammonification preparation, obtains 2 kinds of isomer of equivalent after splitting,, due to the isomer biological activity of (the R)-configuration isomer far below (S)-configuration, there is no utility value.The theoretical yield of traditional technology is up to 50%.The present invention adopts the combination of tartrate and catalyzer, can constantly make the isomer of (R)-configuration change into the 2-amino-butanamide of DL in reaction, then split 2 kinds of isomer that obtain equivalent, so circulation through tartrate, resolution yield is high, in theory can be close to 100%.Below resolution reaction road formula:
(4) be that raw material makes Levetiracetam with (S)-2-amino-butanamide tartrate, have a yield high, the advantage such as quality is good, product purity 〉=99.9%, single impurity≤0.03%, total impurities≤0.1%.
Description of drawings
Fig. 1 is that the 2-bromo-butyric acid makes 2-amino-butanamide solid through ammonolysis reaction, and 2-amino-butanamide solid splits salify through L-(+)-tartrate and makes the reaction formula of S-(+)-2-amino-butanamide tartrate.
Fig. 2 is that S-(+)-2-amino-butanamide tartrate is made the reaction formula of Levetiracetam.
Embodiment
Embodiment 1
A kind of preparation method of Levetiracetam, comprise the steps:
Step 1: 2-amino-butanamide synthetic method.500g ammoniacal liquor and 2-bromo-butyric acid 60g were reacted 3～5 days under-5 ℃～0 ℃, be concentrated into driedly after having reacted, add methyl alcohol 180ml crystallization, oven dry, obtain 2-amino-butanamide white solid 33 grams, molar yield 〉=90%.
Step 2: (S)-tartaric synthetic method of 2-amino-butanamide
2-amino-butanamide 30 grams are dissolved in 200ml methyl alcohol, drop into 45 gram L-(+)-tartrate, 0.3 gram salicylic aldehyde, temperature rising reflux 2 hours, crystallisation by cooling, the S-(+) that the suction filtration oven dry obtains-2-amino-butanamide tartrate 67 grams, molar yield 〉=90%
Step 3: the synthetic method of Levetiracetam
S-(+)-2-amino-butanamide tartrate 20 grams drop in the 120ml methylene dichloride, add anhydrous sodium sulphate 10 grams, and Tetrabutyl amonium bromide 0.1g, add powdered potassium hydroxide 25g.Control temperature below 5 ℃, drip 4-chlorobutanoylchloride 12g, drip off rear about 0 ℃ insulation 5 hours.Reacted rear filtration, filtrate decompression reclaims dichloromethane solvent, adds acetone recrystallization in resistates, dries to obtain Levetiracetam 12g, molar yield 〉=88%, and fusing point: 116 ℃-120 ℃, purity 〉=99.9%, single impurity≤0.03%, total impurities≤0.1%.
Embodiment 2
A kind of preparation method of Levetiracetam, comprise the steps:
Step 1 is identical with the step 1 in embodiment 1.
Step 2: (S)-tartaric synthetic method of 2-amino-butanamide
2-amino-butanamide 30 grams are dissolved in 200ml methyl alcohol, drop into 45 gram L-(+)-tartrate, 0.26 gram phenyl aldehyde, temperature rising reflux 2 hours, crystallisation by cooling, the S-(+) that the suction filtration oven dry obtains-2-amino-butanamide tartrate 67 grams, molar yield 〉=90%
Step 3: the synthetic method of Levetiracetam
S-(+)-2-amino-butanamide tartrate 20 grams drop in dimethyl tertbutyl ether 120ml, add anhydrous sodium sulphate 10 grams, and Tetrabutyl amonium bromide 0.1g, add powdered sodium hydroxide 18g.Control temperature below 5 ℃, drip 4-chlorobutanoylchloride 12g, drip off rear about 0 ℃ insulation 5 hours.Reacted rear filtration, filtrate decompression reclaims dichloromethane solvent, adds acetone recrystallization in resistates, dries to obtain Levetiracetam 12g, molar yield 〉=88%, and fusing point: 116 ℃-120 ℃, purity 〉=99.9%, single impurity≤0.03%, total impurities≤0.1%.
Embodiment 3
A kind of preparation method of Levetiracetam, comprise the steps:
Step 1 is identical with step 1 and step 2 in embodiment 1 with step 2.
Step 3: the synthetic method of Levetiracetam
S-(+)-2-amino-butanamide tartrate 20 grams drop in acetonitrile 120ml, add anhydrous sodium sulphate 10 grams, and Tetrabutyl amonium bromide 0.1g, add powdered sodium hydroxide 18g.Control temperature below 5 ℃, drip 4-chlorobutanoylchloride 12g, drip off rear about 0 ℃ insulation 5 hours.Reacted rear filtration, filtrate decompression reclaims dichloromethane solvent, adds acetone recrystallization in resistates, dries to obtain Levetiracetam 12g, molar yield 〉=88%, and fusing point: 116 ℃-120 ℃, purity 〉=99.9%, single impurity≤0.03%, total impurities≤0.1%.
Claims (3)
1. the preparation method of a Levetiracetam, is characterized in that, comprises the steps:
(1) take the 2-bromo-butyric acid as raw material, be concentrated into driedly after ammonolysis reaction, add methanol crystallization, oven dry, make 2-amino-butanamide solid;
(2) with 2-amino-butanamide dissolution of solid in methyl alcohol,, take the phenyl aldehyde of salicylic aldehyde or 0.01～0.5 mole as catalyzer, split salify through L-(+)-tartrate and make S-(+)-2-amino-butanamide tartrate;
(3) S-(+)-2-amino-butanamide tartrate drops in aprotic solvent, add anhydrous sodium sulphate, Tetrabutyl amonium bromide, under alkaline condition, with filtration after the reaction of 4-chlorobutanoylchloride, after filtrate decompression has been reclaimed aprotic solvent, add acetone recrystallization in residual filtrate, dry to obtain the Levetiracetam solid;
Raw material 2-bromo-butyric acid in described step (1) is 1 mole, and the ammonia in ammonolysis reaction is ammoniacal liquor or liquefied ammonia more than 5 moles; The temperature of ammonolysis reaction is-5 ℃～0 ℃; Reaction times is 3～5 days.
2. the preparation method of a kind of Levetiracetam according to claim 1, it is characterized in that: the L-(+) in described step (2)-tartrate is 0.5～1.5 mole, salicylic aldehyde is 0.01～0.5 mole.
3. the preparation method of a kind of Levetiracetam according to claim 1, it is characterized in that: the alkali in described step (3) is potassium hydroxide or the sodium hydroxide more than 4 moles; Described aprotic solvent is a kind of in methylene dichloride, dimethyl tertbutyl ether or acetonitrile; Described temperature of reaction is-5 ℃～0 ℃, reacts complete rear insulation 5 hours.
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| CN105198768B (en) * | 2015-08-25 | 2017-07-04 | 江苏中邦制药有限公司 | A kind of synthetic method of 2 amino-butanamide |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4696943A (en) * | 1984-05-15 | 1987-09-29 | U C B Societe Anonyme | (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide |
| CN101130504A (en) * | 2006-08-25 | 2008-02-27 | 雅本化学（苏州）有限公司 | Synthesis, split and racemization of chirality medicament levetiracetam midbody (S)-(+)-2-amido butyramide hydrochlorate |
| CN102020584A (en) * | 2010-11-25 | 2011-04-20 | 浙江沙星医药化工有限公司 | Method for synthesizing intermediate L-2-aminobutyrylamide hydrochloride of chiral drug levetiracetam |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4696943A (en) * | 1984-05-15 | 1987-09-29 | U C B Societe Anonyme | (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide |
| CN101130504A (en) * | 2006-08-25 | 2008-02-27 | 雅本化学（苏州）有限公司 | Synthesis, split and racemization of chirality medicament levetiracetam midbody (S)-(+)-2-amido butyramide hydrochlorate |
| CN102020584A (en) * | 2010-11-25 | 2011-04-20 | 浙江沙星医药化工有限公司 | Method for synthesizing intermediate L-2-aminobutyrylamide hydrochloride of chiral drug levetiracetam |
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Denomination of invention: A preparation method of levetiracetam Effective date of registration: 20230103 Granted publication date: 20131113 Pledgee: Zhejiang Taizhou Jiaojiang Rural Commercial Bank Co.,Ltd. Zhang'an sub branch Pledgor: ZHEJIANG JIANGBEI PHARMACEUTICAL Co.,Ltd. Registration number: Y2023330000016 |