CN102584622A - Preparation method of L-2-aminobutanamide hydrochloride - Google Patents
Preparation method of L-2-aminobutanamide hydrochloride Download PDFInfo
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Abstract
The invention provides a preparation method of L-2-aminobutanamide hydrochloride. The method comprises the following steps: based on crude DL-2-aminobutanamide as a starting raw material, reacting with aromatic aldehyde to form DL-Schiff-base, separating, dissociating, and salifying to obtain L-2-aminobutanamide hydrochloride, wherein the Schiff base can be directly separated by using L-tartaric acid, the chiral purity ee value of the product is no less than 99%, the quality is stable, and the separation mother liquor can be recycled through racemization. According to the invention, the raw materials used in each step of the method are cheap and available, the unit operations are simple and safe, the post-treatment is convenient, the requirements on the equipment are low and the method is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation of pharmaceutical intermediate, be specifically related to a kind of preparation method of chiral drug UCB-L 059 midbody L-2-amino-butanamide hydrochloride.
Background technology
UCB-L 059 (Levetiracetam) is a kind of novel antiepileptic drug, all can reduce the epilepsy partial seizures as assisting therapy or single therapy.Obtained drugs approved by FDA in 1999, the assisting therapy of the partial seizures that is used to be grown up, the assisting therapy that its oral tablet in 2005 and solution are got permission to be used for 4 years old and above children and youth epilepsy is shown effect first.Go on the market in China's approval in March, 2007.These article have the unique effect mechanism that is different from other antiepileptic drugs; It is synaptophysin SV2A bonded antiepileptic drug in only so far confirmation and the presynaptic nerve ending; Its with SV2A combine can suppress the paradoxical discharge in the epilepsy loop, thereby the blocking-up epileptic seizures.These article have that bioavailability height, pharmacokinetics are linear, protein binding rate is low, liver metabolism is few, can obtain characteristics such as stabilised blood concentration and drug interaction be little fast, are that clinical application is than safe drugs.
UCB 6474 has R, two kinds of enantiomers of S, and dextrorotatory form has only slight or unconspicuous drug action for suppressing epileptic seizures, and UCB-L 059 then is a kind of antiepileptic drug safely and efficiently.The synthetic key of UCB-L 059 is the optical purity of control levoisomer in reaction process.
The patent No. of UCB. S.A. (BE) Bruxelles Belgium is that the patent of US4696943 is mentioned UCB-L 059 first; And with (R, S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid is a raw material, in solvent benzol, splits with (R)-(+)-Alpha-Methyl benzylamine; Obtain (S)-alpha-ethyl-2-oxo-the 1-pyrrolidine acetic acid; And then amidation, obtain UCB-L 059, shown in following synthetic route.This method has not only been used hypertoxic solvent benzol, should avoid the use of in the industrial production, and the optical purity of the compound that obtains of this method is lower.
Usually adopt two kinds of methods to synthesize in the later patents, a kind of is that the optically active amino acid of employing is starting raw material, and another kind is that salify splits in building-up process.
The patent No. is that disclosing with the L-methionine(Met) in the patent document of CN101550099 is raw material, through the hydroxylation of first sulfydryl, and amino acidylate, the amidation of carboxylic acid, in the method for preparing UCB-L 059 through steps such as cyclizations.Concrete synthetic route is as follows, and visible this method has been used hypertoxic methyl iodide.
The patent No. is that to disclose with the L-Threonine be raw material to the patent document of CN101550100; Prepare the method for UCB-L 059 through steps such as over-churning, halo, dehalogenation, acidylate, cyclizations; Concrete synthetic route is as follows, and the shortcoming of this method is that synthesising reacting time is longer.
The patent No. be the patent document of EP1566376 to disclose with the L-2-propalanine be raw material, through the method that esterification, ammonia are separated, salify, cyclization four-step reaction prepare UCB-L 059, concrete synthetic route is as follows.
Publication number be the patent document of WO03014080 to disclose with the L-2-propalanine be raw material, through esterification, take off HBr, close ring, ammonia is separated the method that four-step reaction prepares UCB-L 059, concrete synthetic route is as follows.
Though above two lines step is few, starting raw material L-2-propalanine costs an arm and a leg, and cost is higher.
The L-2-amino-butanamide hydrochloride is the key intermediate of UCB-L 059 building-up process, important chiral source.Can behind synthetic L-2-amino-butanamide hydrochloride, close ring preparation UCB-L 059 with the 4-chlorobutanoylchloride.The patent No. is the patent document of CN1583721A, is that raw material is when splitting, because the existence of alkali with racemization DL-2-amino-butanamide hydrochloride shown in the following synthetic route; Like sodium hydroxide; Make the inorganic salts of quite a few, like sodium-chlor, sodium tartrate etc. can precipitate with product simultaneously separates out; Cause separation difficulty, the product purity that obtains is not high.And the isomer biological activity of D-form does not have utility value far below the isomer of L-configuration, does not carry out recycling.
The patent No. is that the patent document of CN101130504B discloses with the 2-bromo-butyric acid is that raw material obtains the 2-propalanine through amination in ammoniacal liquor; Separate the free alkali DL-2-amino-butanamide bullion that obtains DL through esterification, ammonia; Adopt the method for half amount fractionation again, obtain the method for optically active L-2-amino-butanamide hydrochloride.And carried out the racemization recycling to splitting mother liquor.Concrete synthetic route is as follows.But in actual production, find to make a big impact for follow-up fractionation operation, cause product suction filtration and quality unstable, receive certain limitation in the production because DL-2-amino-butanamide bullion contains more unknown impuritie.
Summary of the invention
The objective of the invention is to overcome the deficiency of above-mentioned prior art, the preparation method of a kind of purity height, high, the stay-in-grade L-2-amino-butanamide hydrochloride of yield is provided.
For achieving the above object, the present invention adopts following technical scheme:
A kind of preparation method of L-2-amino-butanamide hydrochloride shown in following synthetic route, comprises the steps:
1. purifying: the DL-2-amino-butanamide bullion of DL is soluble in water, add aromatic aldehyde, in-10～50 ℃ of reactions 1～10 hour, form schiff bases and separate out, to filter, drying obtains the schiff bases of the DL of purifying;
2. split: the schiff bases of DL is dissolved in organic solvent, in-10～60 ℃, splits with resolving agent L-tartrate, solid-liquid separation obtains optically active L-2-amino-butanamide L-tartrate solid and splits mother liquor;
3. free salify: L-2-amino-butanamide L-tartrate is suspended in the organic solvent, feeds ammonia, stirred 1～24 hour to saturated; Filter, filtrating feeds hydrogen chloride gas at-10～40 ℃, regulates pH=1～5; Filter, obtain the L-2-amino-butanamide hydrochloride after the drying treatment.
Further, the aromatic aldehyde of said step in 1. has following structure: Ar-CHO, and wherein Ar is an aryl.
Further, said aryl comprises phenyl, monosubstituted phenyl or polysubstituted phenyl.
Further, said step 1. in DL-2-amino-butanamide bullion and the weight ratio of water of DL be 1: 1～100, the DL-2-amino-butanamide bullion of DL and the mol ratio of aromatic aldehyde are 1: 0.8～2.
Further, said step 2. and the organic solvent 3. be in anhydrous methanol, absolute ethyl alcohol, anhydrous propyl alcohol, anhydrous isopropyl alcohol, anhydrous normal butyl alcohol and the anhydrous tertiary butanol one or more.
Further, said step 2. in schiff bases and the weight ratio of organic solvent of DL be 1: 1～50.
Further, said method also comprises 4. racemization: mineral alkali or organic bases are added split mother liquor ,-10～60 ℃ of stirring reactions 1～24 hour; Underpressure distillation is steamed and is desolventized; Obtain the schiff bases bullion of DL, bullion adds in the entry in-10～50 ℃ of following stirrings 1～12 hour, filtration; Drying obtains the schiff bases of pure DL.
Further; The mineral alkali of said step in 4. is alkali metal hydroxide or alkaline carbonate, comprises in yellow soda ash, salt of wormwood, cesium carbonate, Quilonum Retard, sodium hydrogencarbonate, saleratus, Pottasium Hydroxide, sodium hydroxide, Lithium Hydroxide MonoHydrate and the hydrated barta one or more; Described organic bases is one or more in sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide, potassium tert.-butoxide, TMAH, tetraethyl ammonium hydroxide, TPAOH and the TBAH.
Further, the mol ratio of organic bases or mineral alkali and fractionation mother liquor is 0.01～0.5: 1.
Further, the schiff bases bullion of the DL of said step in 4. and the weight ratio of water are 1: 1～100.
The invention provides a kind of preparation method of L-2-amino-butanamide hydrochloride, it is a starting raw material with DL-2-amino-butanamide bullion, form the schiff bases of DL with aromatic aldehyde after, through split, free, salify obtains the L-2-amino-butanamide hydrochloride.Wherein, schiff bases can directly split product chiral purity ee value >=99% with L-tartrate; Steady quality splits directly racemization recycling of mother liquor, the inventive method respectively to go on foot starting material cheap and easy to get; Unit operation is simple and safe; Convenient post-treatment, equipment requirements is low, is fit to industrialized production.
Embodiment
In order to make the object of the invention, technical scheme and advantage clearer,, the present invention is further elaborated below in conjunction with embodiment.Should be appreciated that specific embodiment described herein only in order to explanation the present invention, and be not used in qualification the present invention.
Embodiment 1:
1.1 purifying:
In the 1000ml flask, 100g DL-2-amino-butanamide bullion to be dissolved in the 500ml water, is added the 106g phenyl aldehyde, solid is slowly separated out; Continue under the room temperature to stir 5 hours, filter, wash with less water; 30 ℃ of vacuum-dryings of solid obtain the schiff bases 158g of DL, yield 85.0%.
Preferred version as the step of purifying; Aromatic aldehyde can also be for salicylic aldehyde, p-tolualdehyde, to ethylbenzene formaldehyde, 3,4-dimethylbenzaldehyde and 2,4; A kind of in the 6-trimethylbenzaldehyde and several kinds; Wherein, the mol ratio of DL-2-amino-butanamide bullion and aromatic aldehyde can be 1: 0.8～2, be preferably 1: 1～and 1.5; The DL-2-amino-butanamide bullion of DL and the weight ratio of water can be 1: 1～100, be preferably 1: 5～and 20.
1.2 split:
In the 1000ml flask, add schiff bases 150g, absolute ethyl alcohol 500ml; Stirring makes the solid dissolving, adds 30g L-tartrate/150ml ethanol solution at 20～25 ℃, 20～25 ℃ of reactions 6 hours; Filter, use a small amount of absolute ethanol washing, 70 ℃ of vacuum-dryings of solid are to constant weight; Obtain L-2-amino-butanamide tartrate solid 63.0g, yield 44.5%.
Preferred version as splitting step; Organic solvent can also be selected one or more in anhydrous methanol, anhydrous propyl alcohol, anhydrous isopropyl alcohol, anhydrous normal butyl alcohol and the anhydrous tertiary butanol; Wherein the weight ratio of the schiff bases of DL and organic solvent is 1: 1～50, and first-selection is 1: 5～10.
1.3 free salify:
In the 500ml flask, add L-2-amino-butanamide tartrate 60g, absolute ethyl alcohol 300ml is cooled to 0～5 ℃, feeds ammonia to saturated, continues under the room temperature to stir 10 hours, filters, and uses a small amount of absolute ethanol washing.Filtrating is cooled to 0～5 ℃, and Dropwise 35 % ethanol solution hydrochloride is regulated pH=1～5, filters; Use a small amount of absolute ethanol washing, 60～70 ℃ of vacuum-dryings of solid obtain L-2-amino-butanamide ite 42.3g to constant weight; Yield 91%, chemical purity 99.7%, optical purity ee value 99.5%.
1.4 racemization:
The mother liquor 665ml that embodiment 1.2 is obtained adds in the 1000ml flask, adds sodium ethylate 2.95 grams, is heated to 45～50 ℃, reacts 2 hours; Concentrating under reduced pressure reclaims solvent, and residual solution adds 400ml water, and solid is slowly separated out; Continue under the room temperature to stir 5 hours, filter, wash with less water; 30 ℃ of vacuum-dryings of solid obtain the schiff bases 68.5g of DL, yield 83%.
Preferred version as the racemization step; Mineral alkali is alkali metal hydroxide or alkaline carbonate, can select in yellow soda ash, salt of wormwood, cesium carbonate, Quilonum Retard, sodium hydrogencarbonate, saleratus, Pottasium Hydroxide, sodium hydroxide, Lithium Hydroxide MonoHydrate and the hydrated barta one or more particularly; Organic bases can be selected a kind of in sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide, potassium tert.-butoxide, TMAH, tetraethyl ammonium hydroxide, TPAOH and the TBAH and several kinds, is preferably sodium methylate, sodium ethylate.Wherein, the consumption of organic bases or mineral alkali can be 0.01～0.5: 1 with the mol ratio that splits mother liquor, is preferably 0.01～0.1: 1.
As the preferred version of racemization step, the schiff bases bullion of the DL that racemization obtains and the weight ratio of water can be 1: 1～100, be preferably 1: 5～and 20.
Embodiment 2:
2.1 purifying:
In the 1000ml flask, 100g DL-2-amino-butanamide bullion is dissolved in the 650ml water, add the 106g phenyl aldehyde, solid is slowly separated out; Continue under the room temperature to stir 5 hours, filter, wash with less water; 30 ℃ of vacuum-dryings of solid obtain the schiff bases 162g of DL, yield 87.1%.
2.2 split:
In the 1000ml flask, add schiff bases 150g, anhydrous methanol 500ml; Stirring makes the solid dissolving, adds 30g L-tartrate/150ml absolute methanol solution at 20～25 ℃, 20～25 ℃ of reactions 6 hours; Filter, with a small amount of anhydrous methanol washing, 60 ℃ of vacuum-dryings of solid are to constant weight; Obtain L-2-amino-butanamide tartrate solid 58.8g, yield 41.5%.
2.3 free salify:
In the 500ml flask, add L-2-amino-butanamide tartrate 50g, absolute ethyl alcohol 250ml is cooled to 0～5 ℃, feeds ammonia to saturated, continues under the room temperature to stir 10 hours, filters, and uses a small amount of absolute ethanol washing.Filtrating is cooled to 0～5 ℃, and Dropwise 35 % ethanol solution hydrochloride is regulated pH=1～5, filters; Use a small amount of absolute ethanol washing, 60～70 ℃ of vacuum-dryings of solid obtain L-2-amino-butanamide hydrochloride 37.3g to constant weight; Yield 95%, chemical purity 99.2%, optical purity ee value 99.6%.
2.4 racemization:
The mother liquor 670ml that embodiment 2.2 is obtained adds in the 1000ml flask, adds sodium methylate 1.28 grams, is heated to 35～40 ℃, reacts 5 hours; Concentrating under reduced pressure reclaims solvent, and residual solution adds 400ml water, and solid is slowly separated out; Continue under the room temperature to stir 5 hours, filter, wash with less water; 30 ℃ of vacuum-dryings of solid obtain the schiff bases 74.5g of DL, yield 85%.
Embodiment 3:
3.1 purifying:
In the 1000ml flask, 100g DL-2-amino-butanamide bullion is dissolved in the 650ml water, add the 122g phenyl aldehyde, solid is slowly separated out; Continue under the room temperature to stir 5 hours, filter, wash with less water; 30 ℃ of vacuum-dryings of solid obtain the schiff bases 187g of DL, yield 93.0%.
3.2 split:
In the 1000ml flask, add schiff bases 180g, absolute ethyl alcohol 500ml; Stirring makes the solid dissolving, adds 33g L-tartrate/150ml ethanol solution at 20～25 ℃, 20～25 ℃ of reactions 6 hours; Filter, use a small amount of absolute ethanol washing, 70 ℃ of vacuum-dryings of solid are to constant weight; Obtain L-2-amino-butanamide tartrate solid 70.0g, yield 45.0%.
3.3 free salify:
In the 500ml flask, add L-2-amino-butanamide tartrate 60g, absolute ethyl alcohol 300ml is cooled to 0～5 ℃, feeds ammonia to saturated, continues under the room temperature to stir 10 hours, filters, and uses a small amount of absolute ethanol washing.Filtrating is cooled to 0～5 ℃, and Dropwise 35 % ethanol solution hydrochloride is regulated pH=1～5, filters; Use a small amount of absolute ethanol washing, 60～70 ℃ of vacuum-dryings of solid obtain L-2-amino-butanamide ite 44.2g to constant weight; Yield 94%, chemical purity 99.1%, optical purity ee value 99.3%.
3.4 racemization:
The mother liquor 650ml that embodiment 1.2 is obtained adds in the 1000ml flask, adds sodium ethylate 1.5 grams, is heated to 45～50 ℃, reacts 2 hours; Concentrating under reduced pressure reclaims solvent, and residual solution adds 400ml water, and solid is slowly separated out; Continue under the room temperature to stir 5 hours, filter, wash with less water; 30 ℃ of vacuum-dryings of solid obtain the schiff bases 86.5g of DL, yield 87.0%.
The above is merely preferred embodiment of the present invention, is not to be used for limiting practical range of the present invention; If do not break away from the spirit and scope of the present invention, the present invention is made amendment or is equal to replacement, all should be encompassed in the middle of the protection domain of claim of the present invention.
Claims (10)
1. the preparation method of a L-2-amino-butanamide hydrochloride is characterized in that, comprises the steps: shown in the following synthetic route of said method
1. purifying: the DL-2-amino-butanamide bullion of DL is soluble in water, add aromatic aldehyde, in-10～50 ℃ of reactions 1～10 hour, form schiff bases and separate out, to filter, drying obtains the schiff bases of the DL of purifying;
2. split: the schiff bases of DL is dissolved in organic solvent, in-10～60 ℃, splits with resolving agent L-tartrate, solid-liquid separation obtains optically active L-2-amino-butanamide L-tartrate solid and splits mother liquor;
3. free salify: L-2-amino-butanamide L-tartrate is suspended in the organic solvent, feeds ammonia, stirred 1～24 hour to saturated; Filter, filtrating feeds hydrogen chloride gas at-10～40 ℃, regulates pH=1～5; Filter, obtain the L-2-amino-butanamide hydrochloride after the drying treatment.
2. the preparation method of a kind of L-2-amino-butanamide hydrochloride according to claim 1 is characterized in that, the aromatic aldehyde of said step in 1. has following structure: Ar-CHO, and wherein Ar is an aryl.
3. the preparation method of a kind of L-2-amino-butanamide hydrochloride according to claim 2 is characterized in that, said aryl comprises phenyl, monosubstituted phenyl or polysubstituted phenyl.
4. the preparation method of a kind of L-2-amino-butanamide hydrochloride according to claim 1; It is characterized in that; Said step 1. in DL-2-amino-butanamide bullion and the weight ratio of water of DL be 1: 1～100, the DL-2-amino-butanamide bullion of DL and the mol ratio of aromatic aldehyde are 1: 0.8～2.
5. the preparation method of a kind of L-2-amino-butanamide hydrochloride according to claim 1; It is characterized in that, said step 2. and the organic solvent 3. be in anhydrous methanol, absolute ethyl alcohol, anhydrous propyl alcohol, anhydrous isopropyl alcohol, anhydrous normal butyl alcohol and the anhydrous tertiary butanol one or more.
6. the preparation method of a kind of L-2-amino-butanamide hydrochloride according to claim 1 is characterized in that, said step 2. in schiff bases and the weight ratio of organic solvent of DL be 1: 1～50.
7. the preparation method of a kind of L-2-amino-butanamide hydrochloride according to claim 1 is characterized in that, said method also comprises 4. racemization: mineral alkali or organic bases are added the fractionation mother liquor;-10～60 ℃ of stirring reactions 1～24 hour, underpressure distillation was steamed and is desolventized, and obtains the schiff bases bullion of DL; Bullion adds in the entry-10～50 ℃ of following stirrings 1～12 hour; Filter, drying obtains the schiff bases of pure DL.
8. the preparation method of a kind of L-2-amino-butanamide hydrochloride according to claim 7; It is characterized in that; The mineral alkali of said step in 4. is alkali metal hydroxide or alkaline carbonate, comprises in yellow soda ash, salt of wormwood, cesium carbonate, Quilonum Retard, sodium hydrogencarbonate, saleratus, Pottasium Hydroxide, sodium hydroxide, Lithium Hydroxide MonoHydrate and the hydrated barta one or more; Described organic bases is one or more in sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide, potassium tert.-butoxide, TMAH, tetraethyl ammonium hydroxide, TPAOH and the TBAH.
9. the preparation method of a kind of L-2-amino-butanamide hydrochloride according to claim 8 is characterized in that, the mol ratio of organic bases or mineral alkali and fractionation mother liquor is 0.01～0.5: 1.
10. the preparation method of a kind of L-2-amino-butanamide hydrochloride according to claim 7 is characterized in that, the schiff bases bullion of the DL of said step in 4. and the weight ratio of water are 1: 1～100.
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Cited By (5)
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| CN102863354A (en) * | 2012-09-06 | 2013-01-09 | 浙江华海药业股份有限公司 | Method for dynamically splitting 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 |
| CN109503408A (en) * | 2019-01-07 | 2019-03-22 | 宁波赜军医药科技有限公司 | A kind of method for splitting of (S)-(+) -2- amino-butanamide hydrochloride |
| CN109678752A (en) * | 2018-12-27 | 2019-04-26 | 南京红杉生物科技有限公司 | A kind of method of asymmetric transformation synthesis L-2- amino-butanamide hydrochloride |
| CN113582903A (en) * | 2021-08-25 | 2021-11-02 | 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 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863354A (en) * | 2012-09-06 | 2013-01-09 | 浙江华海药业股份有限公司 | Method for dynamically splitting 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 |
| CN109678752A (en) * | 2018-12-27 | 2019-04-26 | 南京红杉生物科技有限公司 | A kind of method of asymmetric transformation synthesis L-2- amino-butanamide hydrochloride |
| CN109678752B (en) * | 2018-12-27 | 2021-11-16 | 南京红杉生物科技有限公司 | Method for synthesizing L-2-aminobutanamide hydrochloride by asymmetric transformation |
| CN109503408A (en) * | 2019-01-07 | 2019-03-22 | 宁波赜军医药科技有限公司 | A kind of method for splitting of (S)-(+) -2- amino-butanamide hydrochloride |
| CN109503408B (en) * | 2019-01-07 | 2021-12-21 | 宁波赜军医药科技有限公司 | Resolution method of (S) - (+) -2-aminobutanamide hydrochloride |
| CN113582903A (en) * | 2021-08-25 | 2021-11-02 | 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 |
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| CN102584622B (en) | 2013-08-14 |
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