CN102020584A - Method for synthesizing intermediate L-2-aminobutyrylamide hydrochloride of chiral drug levetiracetam - Google Patents
Method for synthesizing intermediate L-2-aminobutyrylamide hydrochloride of chiral drug levetiracetam Download PDFInfo
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Abstract
The invention belongs to the field of the preparation of chiral drug intermediates and particularly relates to a method for synthesizing a intermediate L-2-aminobutyrylamide hydrochloride of chiral drug levetiracetam. The method is characterized by taking 2-bromobutyric acid as a starting raw material and comprising the steps of: firstly, preparing a 2-bromobutyric amide intermediate, reacting the 2-bromobutyric amide intermediate to generate DL-2-aminobutyrylamide, and finally, splitting and salifying the DL-2-aminobutyrylamide to synthesize the L-2-aminobutyrylamide hydrochloride. Compared with the traditional synthesis method, the method has the advantages of mild reaction conditions, low cost, higher yield, greatly improved process safety, cheap and easily-obtained raw materials, simple unit operations and low requirements on equipment and is suitable for industrial large-scale production, amidation reaction is carried out at normal temperature and normal pressure, and the reaction is easy to control.
Description
Technical field
The invention belongs to chiral drug intermediate preparation field, be specially a kind of synthetic method of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride.
Background technology
The preparation method of chiral drug Levetiracetam has bibliographical information, introduced the synthetic of this compound respectively as EP1566376, CN1015541B and CN1583721A, main route has, the one, be starting raw material with the L-2-aminobutyric acid, through esterification, ammonia separate, cyclization or cyclization, esterification, ammonia is separated and is made target product again.Though this route steps is few, starting raw material L-2-aminobutyric acid costs an arm and a leg, and cost is higher.The 2nd, be starting raw material with positive propionic aldehyde, through Strake reaction, hydrolysis, fractionation, esterification, ammonia separate, the cyclization six-step process prepares target compound, this method reactions steps is long, yield only is 4.7%, CN1583721A improves this route, different positive propionic aldehyde, sodium cyanide are starting raw material, through Strake reaction, hydrolysis, fractionation, cyclization four steps preparation target compound, use this method, the yield of product is improved, but this method has adopted the deadly poisonous compound sodium cyanide, and is higher to safety of operators, three wastes processing and environmental requirement.
The L-2-amino-butanamide hydrochloride is the important intermediate of synthesis of chiral medicine Levetiracetam.In CN101130504A, reported that with the 2-bromo-butyric acid be starting raw material, separate, split and make target product through ammonification, esterification, ammonia.2-bromo-butyric acid and ammoniacal liquor generation aminating reaction generate the 2-aminobutyric acid, because brometo de amonio that generates and 2-aminobutyric acid are difficult in separation, thus need be refining, reaction yield is low, about 70% molar yield.In the reaction that ammonia is separated, be to generate 2-aminobutyric acid methyl esters earlier in addition, obtain DL 2-amino-butanamide with ammonia gas react then by the 2-aminobutyric acid, speed of reaction is slow, logical ammonia react 24 hours, and logical sometimes ammonia produces pressure, higher to equipment requirements, influential to process safety.Therefore to exist yield low for this route, the defective that process safety is relatively poor.Seek and a kind ofly new can realize scale operation, yield is higher, security is higher, the synthetic method of L-2-amino-butanamide hydrochloride becomes the problem that presses for solution.
Summary of the invention
At problems of the prior art, the object of the present invention is to provide a kind of technical scheme of synthetic method of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride, its amidate action carries out at normal temperatures and pressures, process safety improves greatly, starting material are cheap and easy to get, unit operation is simple, and equipment requirements is low, is fit to industrialized production.
The synthetic method of described a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride, it is characterized in that: with the 2-bromo-butyric acid is starting raw material, prepare 2-bromine butyramide intermediate earlier, 2-bromine butyramide intermediate generates DL 2-amino-butanamide by reaction again, realize the synthetic of L-2-amino-butanamide hydrochloride by splitting salify at last, synthetic line is as follows:
Concrete steps are:
(1) amidate action takes place in 2-bromo-butyric acid and ammoniacal liquor under the thionyl chloride effect, generates 2-bromine butyramide;
(2) reaction of 2-bromine butyramide and ammoniacal liquor generates DL 2-amino-butanamide;
(3) DL 2-amino-butanamide is by the method for half amount fractionation, be combined into L-tartrate and salt out, reach the purpose of separation and purification, remove resolving agent through alkalization and obtain optically active free alkali, and then salify obtains optically active L-2-amino-butanamide hydrochloride.
The synthetic method of described a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride, it is characterized in that 2-bromo-butyric acid described in the step (1) and ammoniacal liquor under the thionyl chloride effect amidate action take place, the ether solvent that reaction is adopted is a kind of in ether, methyl tertiary butyl ether, the diisopropyl ether.
The synthetic method of described a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride, the mol ratio that it is characterized in that the 2-bromo-butyric acid described in the step (1), thionyl chloride, ammoniacal liquor is 1:1:2, temperature of reaction is-5～20 ℃, reaction times is 2～10 hours, and reaction pressure is a normal pressure.
The synthetic method of described a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride, the mol ratio that it is characterized in that the 2-bromo-butyric acid described in the step (1), thionyl chloride, ammoniacal liquor is 1:1:2, temperature of reaction is 5～10 ℃, reaction times is 4～6 hours, and reaction pressure is a normal pressure.
The synthetic method of described a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride, it is characterized in that in the preparation of the DL 2-amino-butanamide described in the step (2) that 2-bromine butyramide and ammoniacal liquor reaction back adding solvent methanol carry out crystallization and obtain DL 2-amino-butanamide.
The synthetic method of described a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride is characterized in that 2-bromine butyramide described in the step (2) and ammoniacal liquor temperature of reaction are 10～60 ℃, and the reaction times is 10～20 hours.
The synthetic method of described a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride is characterized in that 2-bromine butyramide described in the step (2) and ammoniacal liquor temperature of reaction are 35～45 ℃, and the reaction times is 11～12 hours.
Patent of the present invention has the following advantages:
(1) adopted new synthetic route, the 2-bromo-butyric acid is that raw material obtains 2-bromine butyramide through amidate action earlier, obtains DL 2-amino-butanamide by the ammonia substitution reaction then, obtains the L-2-amino-butanamide hydrochloride by fractionation at last;
(2) compare with existing synthetic method, amidate action carries out at normal temperatures and pressures, the reaction conditions gentleness, and reaction is easy to control, cost is low, and yield is higher, and process safety improves greatly, and starting material are cheap and easy to get, unit operation is simple, and equipment requirements is low, is fit to industrialized production.
Embodiment
The present invention will be further described below in conjunction with specific embodiment, but protection scope of the present invention is not limited thereto:
1) the 2-bromo-butyric acid is synthetic
Embodiment one:
In the reaction flask of 1000ml, add 83.5g 2-bromo-butyric acid, 125g 28% ammoniacal liquor and 500ml ether cool to-5 ℃, stir down slowly Dropwise 5 9.5g thionyl chloride, drip off back insulated and stirred reaction 10 hours.After having reacted, layering, organic layer washing is concentrated into driedly, obtains white solid 2-bromine butyramide 73g, yield 88%, purity 98.5%.
Embodiment two:
In the reaction flask of 2000ml, add 167g 2-bromo-butyric acid, 250g 28% ammoniacal liquor and 1000ml methyl tertiary butyl ether, cool to 0 ℃, stir down and slowly drip the 119g thionyl chloride, drip off the back and be warming up to 20 ℃ naturally, insulated and stirred reaction 2 hours, after reacting completely, layering, organic layer washing, be concentrated into dried, obtain white solid 2-bromine butyramide 143g, yield 86%, purity 98.9%.
Embodiment three:
In the reaction flask of 2000ml, add 167g 2-bromo-butyric acid, 250g 28% ammoniacal liquor and 1000ml methyl tertiary butyl ether, cool to 0 ℃, stir down and slowly drip the 119g thionyl chloride, drip off the back and be warming up to 10 ℃ naturally, insulated and stirred reaction 4 hours, after reacting completely, layering, organic layer washing, be concentrated into dried, obtain white solid 2-bromine butyramide 148g, yield 89.2%, purity 99.2%.
Embodiment four:
In the reaction flask of 1000ml, add 83.5g 2-bromo-butyric acid, 125g 28% ammoniacal liquor and 500ml diisopropyl ether cool to 0 ℃, stir down slowly Dropwise 5 9.5g thionyl chloride, drip off back 5 ℃ of insulated and stirred reaction 6 hours.After having reacted, layering, organic layer washing is concentrated into driedly, obtains white solid 2-bromine butyramide 75g, yield 90.4%, purity 99.1%.
2) DL 2-aminobutyric acid is synthetic
Embodiment one:
In the reaction flask of 1000ml, add 166g 2-bromine butyramide, 500g 28% ammoniacal liquor cools to 10 ℃, stirring reaction 20 hours, after reacting completely, be evaporated to driedly, residual solids is made with extra care with methyl alcohol, obtains white crystals DL 2-amino-butanamide 75g, yield 73.5%, content 99.0%.
Embodiment two:
In the reaction flask of 2000ml, add 332g 2-bromine butyramide, 1000g 28% ammoniacal liquor is heated to 35 ℃, stirring reaction 12 hours after reacting completely, is evaporated to driedly, and residual solids is made with extra care with methyl alcohol, obtain white crystals DL 2-amino-butanamide 169g, yield 83%, content 99.3%.
Embodiment three:
In the reaction flask of 2000ml, add 332g 2-bromine butyramide, 1000g 28% ammoniacal liquor is heated to 45 ℃, stirring reaction 11 hours, after reacting completely, be evaporated to driedly, residual solids is made with extra care with methyl alcohol, obtains white crystals DL 2-amino-butanamide 167g, yield 81.9%, content 99.1%.
Embodiment four:
In the reaction flask of 1000ml, add 166g 2-bromine butyramide, 500g 28% ammoniacal liquor is heated to 60 ℃, stirring reaction 10 hours after reacting completely, is evaporated to driedly, and residual solids is made with extra care with methyl alcohol, obtain white crystals DL 2-amino-butanamide 72g, yield 70.6%, content 98.6 %.
3) the L-2-amino-butanamide hydrochloride is synthetic
In the reaction flask of 1000ml, add the 2-amino-butanamide of 80g DL, 480ml 95% ethanol is heated to 60 ℃, add 57g L-tartrate, stirred 2 hours, and filtered, with an amount of 95% washing with alcohol, filter cake is a L-2-amino-butanamide L-tartrate solid, filtrate decompression concentrates to remove and desolvates, and the about 43g of residual solution is mainly the D-2-amino-butanamide.
L-2-amino-butanamide L-tartrate solid suspension in ethanol, is fed ammonia to saturated, stirring at room 6-8 hour, filter, be evaporated to about 200ml, drip 30% hydrogenchloride/ethanolic soln, regulate PH=1-2, filter the washing with alcohol solid, vacuum-drying, obtain L-2-amino-butanamide hydrochloride 45.6g, yield 40%, mp:257-258 ℃, purity 99.2%, remaining D-2-amino-butanamide becomes DL 2-amido butyramide again by racemization.
Claims (7)
1. the synthetic method of a chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride, it is characterized in that: with the 2-bromo-butyric acid is starting raw material, prepare 2-bromine butyramide intermediate earlier, 2-bromine butyramide intermediate generates DL 2-amino-butanamide by reaction again, realize the synthetic of L-2-amino-butanamide hydrochloride by splitting salify at last, synthetic line is as follows:
Concrete steps are:
(1) amidate action takes place in 2-bromo-butyric acid and ammoniacal liquor under the thionyl chloride effect, generates 2-bromine butyramide;
(2) reaction of 2-bromine butyramide and ammoniacal liquor generates DL 2-amino-butanamide;
(3) DL 2-amino-butanamide is by the method for half amount fractionation, be combined into L-tartrate and salt out, reach the purpose of separation and purification, remove resolving agent through alkalization and obtain optically active free alkali, and then salify obtains optically active L-2-amino-butanamide hydrochloride.
2. the synthetic method of a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride according to claim 1, it is characterized in that 2-bromo-butyric acid described in the step (1) and ammoniacal liquor under the thionyl chloride effect amidate action take place, the ether solvent that reaction is adopted is a kind of in ether, methyl tertiary butyl ether, the diisopropyl ether.
3. the synthetic method of a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride according to claim 1, the mol ratio that it is characterized in that the 2-bromo-butyric acid described in the step (1), thionyl chloride, ammoniacal liquor is 1:1:2, temperature of reaction is-5～20 ℃, reaction times is 2～10 hours, and reaction pressure is a normal pressure.
4. the synthetic method of a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride according to claim 1, the mol ratio that it is characterized in that the 2-bromo-butyric acid described in the step (1), thionyl chloride, ammoniacal liquor is 1:1:2, temperature of reaction is 5～10 ℃, reaction times is 4～6 hours, and reaction pressure is a normal pressure.
5. the synthetic method of a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride according to claim 1, it is characterized in that in the preparation of the DL 2-amino-butanamide described in the step (2) that 2-bromine butyramide and ammoniacal liquor reaction back adding solvent methanol carry out crystallization and obtain DL 2-amino-butanamide.
6. the synthetic method of a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride according to claim 1, it is characterized in that 2-bromine butyramide described in the step (2) and ammoniacal liquor temperature of reaction are 10～60 ℃, the reaction times is 10～20 hours.
7. the synthetic method of a kind of chiral drug Levetiracetam intermediate L-2-amino-butanamide hydrochloride according to claim 1, it is characterized in that 2-bromine butyramide described in the step (2) and ammoniacal liquor temperature of reaction are 35～45 ℃, the reaction times is 11～12 hours.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295575A (en) * | 2011-08-31 | 2011-12-28 | 浙江华海药业股份有限公司 | Method for performing kinetic resolution on 2-aminobutanamide racemate |
| CN102382027A (en) * | 2011-09-20 | 2012-03-21 | 浙江江北药业有限公司 | Method for preparing levetiracetam |
| CN102633675A (en) * | 2012-04-10 | 2012-08-15 | 南京大学 | Method for preparing DL-2-amino butyrylamide |
| CN102898324A (en) * | 2012-10-19 | 2013-01-30 | 阜新龙瑞化工有限责任公司 | Method for preparing (S)-2-aminobutanamide hydrochloride |
| CN103193671A (en) * | 2013-04-05 | 2013-07-10 | 浙江华海药业股份有限公司 | Method for preparing L-2-aminobutanamide hydrochloride |
| CN106187809A (en) * | 2016-07-20 | 2016-12-07 | 南通雅本化学有限公司 | A kind of synthesis technique of levetiracetam intermediate |
| CN111825593A (en) * | 2020-08-19 | 2020-10-27 | 上海成澄科技有限公司 | Synthetic method of 3-aminopyrrole-2-formamide compound |
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| 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 |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295575A (en) * | 2011-08-31 | 2011-12-28 | 浙江华海药业股份有限公司 | Method for performing kinetic resolution on 2-aminobutanamide racemate |
| CN102382027A (en) * | 2011-09-20 | 2012-03-21 | 浙江江北药业有限公司 | Method for preparing levetiracetam |
| CN102382027B (en) * | 2011-09-20 | 2013-11-13 | 浙江江北药业有限公司 | Method for preparing levetiracetam |
| CN102633675A (en) * | 2012-04-10 | 2012-08-15 | 南京大学 | Method for preparing DL-2-amino butyrylamide |
| CN102898324A (en) * | 2012-10-19 | 2013-01-30 | 阜新龙瑞化工有限责任公司 | Method for preparing (S)-2-aminobutanamide hydrochloride |
| CN103193671A (en) * | 2013-04-05 | 2013-07-10 | 浙江华海药业股份有限公司 | Method for preparing L-2-aminobutanamide hydrochloride |
| CN103193671B (en) * | 2013-04-05 | 2017-10-17 | 浙江华海药业股份有限公司 | A kind of method for preparing the amino-butanamide hydrochlorides of L 2 |
| CN106187809A (en) * | 2016-07-20 | 2016-12-07 | 南通雅本化学有限公司 | A kind of synthesis technique of levetiracetam intermediate |
| CN111825593A (en) * | 2020-08-19 | 2020-10-27 | 上海成澄科技有限公司 | Synthetic method of 3-aminopyrrole-2-formamide compound |
| CN111825593B (en) * | 2020-08-19 | 2023-04-07 | 上海成澄科技有限公司 | Synthetic method of 3-aminopyrrole-2-formamide compound |
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