CN102060744B - Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide - Google Patents
Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- IHLAQQPQKRMGSS-BYPYZUCNSA-N 2-[(4s)-4-hydroxy-2-oxopyrrolidin-1-yl]acetamide Chemical compound NC(=O)CN1C[C@@H](O)CC1=O IHLAQQPQKRMGSS-BYPYZUCNSA-N 0.000 title abstract description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 69
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- 238000001953 recrystallisation Methods 0.000 claims abstract description 35
- 239000003513 alkali Substances 0.000 claims abstract description 25
- WKNMKGVLOWGGOU-UHFFFAOYSA-N 2-aminoacetamide;hydron;chloride Chemical compound Cl.NCC(N)=O WKNMKGVLOWGGOU-UHFFFAOYSA-N 0.000 claims abstract description 19
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 238000000746 purification Methods 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- 239000000243 solution Substances 0.000 claims description 40
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 38
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 32
- 230000002378 acidificating effect Effects 0.000 claims description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 17
- 239000003957 anion exchange resin Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 16
- 235000010755 mineral Nutrition 0.000 claims description 16
- 239000011707 mineral Substances 0.000 claims description 16
- 238000006386 neutralization reaction Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- 125000002091 cationic group Chemical group 0.000 claims description 13
- 239000011347 resin Substances 0.000 claims description 13
- 229920005989 resin Polymers 0.000 claims description 13
- 238000010792 warming Methods 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000003729 cation exchange resin Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 235000017550 sodium carbonate Nutrition 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 150000003440 styrenes Chemical class 0.000 claims description 10
- 239000012141 concentrate Substances 0.000 claims description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims 4
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 19
- 239000003456 ion exchange resin Substances 0.000 abstract description 5
- 229920003303 ion-exchange polymer Polymers 0.000 abstract description 5
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 150000007529 inorganic bases Chemical class 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 26
- 235000019441 ethanol Nutrition 0.000 description 21
- 229960001227 oxiracetam Drugs 0.000 description 10
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 238000007689 inspection Methods 0.000 description 5
- -1 alcohol compound Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- IHLAQQPQKRMGSS-SCSAIBSYSA-N 2-[(4r)-4-hydroxy-2-oxopyrrolidin-1-yl]acetamide Chemical compound NC(=O)CN1C[C@H](O)CC1=O IHLAQQPQKRMGSS-SCSAIBSYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000003925 brain function Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002664 nootropic agent Substances 0.000 description 1
- 230000001777 nootropic effect Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Abstract
The invention discloses a preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide, comprising the following steps of: taking (S)-4-halogen-3-hydroxybutyrate and glycinamide or glycinamide hydrochloride as raw materials to react under the alkali condition through an alcohol solvent so as to obtain coarse products of the (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide; and then carrying out the purification process on the coarse products. The preparation method is characterized in that the reaction under the alkali condition is realized by adding inorganic base in the reaction process in times so as to control a pH value during the reaction to be <=8.5; the reaction is carried out under the condition of heating to flow backing; and the purification process is realized by utilizing ion-exchange resin and the recrystallization. In the invention, the main raw materials are the (S)-4-halogen-3-hydroxybutyrate and the glycinamide hydrochloride, both of which are products on sale; the raw materials are cheap, easily obtained, and environment-friendly without pollution; the preparation of the invention has short reaction period and is convenient and simple to operate; and the HPLC (High Performance Liquid Chromatography) purity of the prepared products of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide is more than 98.5%.
Description
Technical field
The present invention relates to the preparation method of a kind of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide (trade name is (S)-oxiracetam, and is as follows).
Background technology
Oxiracetam be by Italian SmithKline than Qie Mu company in 1974 synthetic nootropics first, by two kinds of isomer (S)-oxiracetam ((S)-oxiracetam) with (R)-oxiracetam (raceme of (R)-oxiracetam) form.(S)-and oxiracetam is a single enantiomer of oxiracetam, chemistry is by name: (S)-and 4-hydroxyl-2-OXo-1-pyrrolidine ethanamide, its chemical structure such as figure below:
Two isomer according to WO93/06826 report oxiracetam are used for the active variant of brain function improving agent, and wherein (S)-oxiracetam is stronger than the activity of (R)-oxiracetam.
The preparation method of (the S)-oxiracetam among the patent WO2005/115978; Wherein (S)-4-chloro-3-butyric ester and G-NH2 react under alkaline condition that to obtain the finished product oxiracetam be to add the alkalescence that alkali is controlled reaction solution through disposable; But, so directly influenced the yield of oxiracetam in strong base solution because oxiracetam is destroyed easily.
In addition; Among the preparation method of (the S)-oxiracetam among the patent WO2005/115978; Reaction can be to carry out under 0～100 ℃ of condition in temperature; But in so wide TR, the efficient phase difference of reaction is very big, and it still can not provide a highest range of reaction temperature of product yield.
In addition, in purifying the finished product oxiracetam, adopt silica gel column chromatography method, the elutriant of use is organic mixed solvent, and quantity of solvent is big, pollutes big and difficult the recovery, and cost is high, and the also suitable suitability for industrialized production of silica gel column chromatography method.
Summary of the invention
The object of the invention just is the method for preparing high purity (S)-oxiracetam that provides a kind of yield high.
The objective of the invention is to realize like this: the preparation method of a kind of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide; It comprises that usefulness (S)-4-halogen-3-butyric ester is that raw material reacts the thick product and this thick purification of product that obtains (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide under polar solvent and alkaline condition, is characterized in that: above-mentioned alkaline condition reaction down is to add mineral alkali to control pH value in the above-mentioned reaction≤8.5 through gradation in above-mentioned reaction process.
In order further to improve the yield of (S)-oxiracetam, above-mentioned reaction is to carry out being warming up under the condition of backflow.
For the ease of suitability for industrialized production, thick purification of product is realized thick product dissolving back through ion exchange resin and recrystallization.
Among the present invention, above-mentioned (S)-4-hydroxyl-thick product of 2-OXo-1-pyrrolidine ethanamide is obtained by above-mentioned (S)-4-halogen-3-butyric ester and G-NH2 reaction; In order to make reactant and product be easy to dissolve and react the convenient processing after accomplishing that above-mentioned polar solvent is preferably alcohol compound.
Above-mentioned (S)-4-halogen-3-butyric ester is the commercial goods, and its structural formula is:
Wherein X represents halogen atom Br or Cl, and R represents the alkyl of 1～2 carbon atom.
G-NH2 in the above-mentioned reaction is preferably glycyl amide hydrochloride; Why preferred glycyl amide hydrochloride is that chemical property is more stable at normal temperatures owing to glycyl amide hydrochloride in the present invention, can guarantee reaction mass like this.
Above-mentioned alcohol compound be in methyl alcohol, ethanol, propyl alcohol, butanols and the Virahol any one or multiple.
Above-mentioned mineral alkali can be selected yellow soda ash, sodium hydrogencarbonate or salt of wormwood.
The mol ratio of above-mentioned raw material (S)-4-halogen-3-butyric ester and glycyl amide hydrochloride is 1.0:0.8～1.2; (S)-and the amount ratio of 4-halogen-3-butyric ester and polar solvent is 1 mole: 600～1000 milliliters.
Above-mentioned thick purification of product be with thick product with water dissolution after through strongly acidic cationic exchange resin and collect, again through in the strongly basic anion exchange resin with the solution of collecting, the pH value of the solution of said collection is accomplished when neutral; Thick product after the solution concentration of collecting that will neutralize then carries out recrystallization to be handled.
Above-mentioned strongly acidic cationic exchange resin is: 001 * 7 strongly acidic styrene type cation exchange resin; Above-mentioned strongly basic anion exchange resin is: 201 * 7 strong-basicity styrene series anion exchange resins.Characteristics such as 001 * 7 strongly acidic styrene type cation exchange resin and 201 * 7 strong-basicity styrene series anion exchange resins have the exchange capacity height, exchange velocity is fast, and physical strength is good are particularly suitable for this reaction and use.
Above-mentioned strongly acidic cationic exchange resin uses the hydrochloric acid soln regeneration of 1 mol of 4 times of volumes, and water is washed till neutrality; Above-mentioned strongly basic anion exchange resin uses the sodium hydroxide solution regeneration of 1 mol of 4 times of volumes, and water is washed till neutrality.
Above-mentioned recrystallization is handled, and promptly adopts ethanol to carry out the recrystallization processing first time, adopts the mixed solvent of Virahol or methanol/acetone to carry out the recrystallization processing second time.
In the above-mentioned first time recrystallization, be dissolved into the thick product after said the concentrating in the ethanol after, can also add a certain amount of activated carbon decolorizing; The weight ratio of the thick product after above-mentioned gac and above-mentioned the concentrating is 1:30～80.
The preparation method of above-mentioned (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide, it specifically comprises following steps:
(a) glycyl amide hydrochloride and part mineral alkali are added in the alcohol compound solvent, the consumption of mineral alkali is 7.3 ± 0.3 with control pH value, is warming up to backflow under stirring, and makes glycyl amide hydrochloride fully free, guarantees sufficient reacting, complete;
(b) progressively drip (S)-4-halogen-3-butyric ester, in the process that drips, add remaining mineral alkali more in batches,, so promptly satisfied reaction conditions, can protect title product not to be destroyed again for alkalescence to control said reaction pH value≤8.5;
(c) drip (S)-4-halogen-3-butyric ester continued back flow reaction; HPLC measures product (S)-4-hydroxyl-termination reaction when 2-OXo-1-pyrrolidine ethanamide content is the highest, with the solution that obtains filter the back concentrate the thick product of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide; Product wherein (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide content mxm. can be confirmed through limited test by those skilled in the art;
(d) aqueous solution with above-mentioned thick product passes through also to collect behind the strongly acidic cationic exchange resin, passes through in the strongly basic anion exchange resin again and the solution of collection;
(e) handle carrying out first time recrystallization with ethanol after the solution concentration after the above-mentioned neutralization, must said product after carrying out recrystallization second time with the mixing solutions of Virahol or methanol/acetone.
In the above-mentioned steps, wherein in (a) step: said backflow is no less than 2 hours; (b) in the step: the said mineral alkali that in batches adds is 5～8 batches; (c) in the step: the said reaction times is 20～28 hours, the said heat filtering that is filtered into; (d) in the step: the aqueous solution of said thick product is pressed thick product: water=1 gram: 0.5～1.2 milliliter, the consumption of said strongly acidic cationic exchange resin is: said thick product: said strongly acidic cationic exchange resin=1 gram: 8～12 milliliters; (e) in the step, the consumption that said use ethanol carries out recrystallization processing for the first time is: the thick product after said the concentrating: ethanol=1 gram: 1.0～3.0 milliliters; The consumption of said second time of recrystallization in handling is: the thick product behind the recrystallization for the first time: Virahol=1 gram: 8.0～15.0 milliliters; Or the thick product behind the recrystallization for the first time: methyl alcohol=1 gram: 1.0～2.0 milliliters, wherein the volume ratio of methyl alcohol and acetone is 1:2～4 in the mixed solvent of methanol/acetone.
The preparation method of above-mentioned (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide, most preferred scheme steps in sequence is:
(a) glycyl amide hydrochloride and part mineral alkali are added in the alcohol compound solvent, control pH value is 7.3 ± 0.3, is warming up to backflow under stirring;
(b) backflow progressively dripped (S)-4-halogen-3-butyric ester later in 2 hours, in the process that drips, divided 5～8 batches to add mineral alkalis, to guarantee said reaction pH value≤8.5;
(c) after dripping (S)-4-halogen-3-butyric ester; Back flow reaction is 20～28 hours again; HPLC measures product (S)-4-hydroxyl-termination reaction when 2-OXo-1-pyrrolidine ethanamide content is the highest, then heat filtering concentrate the thick product of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide;
(d) above-mentioned thick product and water are restrained by 1: obtain thick product solution after 0.5～1.2 milliliter the mixed; This thick product solution is re-used neutralization of 201 * 7 strong-basicity styrene series anion exchange resins and collection through 001 * 7 strongly acidic cationic exchange resin and after collecting, and wherein the consumption of 001 * 7 strongly acidic styrene type cation exchange resin is: said thick product: said 001 * 7 strongly acidic cationic exchange resin=1 gram: 8～12 milliliters;
The solution concentration of (e) above-mentioned neutralization being collected gets thick product; Carry out the recrystallization first time with ethanol; Consumption of ethanol is pressed the thick product after said the concentrating: ethanol=1 gram: 1.0～3.0 milliliters, and after being dissolved into thick product in the ethanol, add activated carbon decolorizing; The weight ratio of the thick product after said gac and said the concentrating is 1:35～55, and the mixing solutions with Virahol or methanol/acetone carries out the recrystallization second time then; The amount ratio of said second time of recrystallization in handling is: the thick product behind the recrystallization for the first time: Virahol=1 gram: 8.0～15.0 milliliters; Or the thick product behind the recrystallization for the first time: methyl alcohol=1 gram: 1.0～2.0 milliliters, wherein the volume ratio of methyl alcohol and acetone is 1:2～4 in the mixing solutions of methanol/acetone.
Adopt (the S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide HPLC purity of the inventive method preparation to reach more than 98.5%.
For beneficial effect of the present invention is described, the inventor has carried out following simultaneous test:
Simultaneous test one: pH value is to the influence of (S)-oxiracetam yield
Test 1: the preparation method of a kind of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide, its concrete steps are:
(a) glycyl amide hydrochloride 55.0g, yellow soda ash 29.2g and absolute ethyl alcohol 500ml are dropped in the reaction flask, control pH value is about 7.4, is warming up to backflow under stirring;
(b) backflow progressively dripped (S)-4-chloro-ethyl 3-hydroxybutanoate 99.6g later in 2 hours, in the process that drips, divided 6 batches to add remaining yellow soda ash 29.1g, controlled the alkali number that at every turn adds through the inspection of pH value, to guarantee said reaction pH value≤8.5;
(c) after dripping (S)-4-halogen-3-butyric ester, back flow reaction is 26 hours again, with the solution heat filtering that obtains concentrate the thick product of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide;
(d) above-mentioned thick product is dissolved in the 100ml water, handles, collect the product part through 001 * 7 strongly acidic styrene type cation exchange resin 800ml.With in 201 * 7 strong-basicity styrene series anion exchange resins with collect the aqueous solution obtain, measure according to the pH of solution and reach at 7.0 ± 0.1 o'clock and judge neutralization and accomplish.
(e) solution concentration is collected in above-mentioned neutralization and do, add ethanol 150ml and heat, dissolve limpid back and add activated carbon 1g decolouring 30 minutes, filter, get white crystals product (S)-oxiracetam 25.0g behind the crystallisation by cooling; (volume ratio: 1/3) the mixed solvent recrystallization gets (S)-oxiracetam 19.0g (HPLC:99.14%) to adopt methanol/acetone again.
Test 2: the preparation method of a kind of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide, its concrete steps are:
(a) glycyl amide hydrochloride 55.0g, yellow soda ash 58.3g and absolute ethyl alcohol 500ml are dropped in the reaction flask, be warming up to backflow under stirring;
(b) backflow progressively dripped (S)-4-chloro-ethyl 3-hydroxybutanoate 99.6g in 2 hours later on;
(c) after dripping (S)-4-halogen-3-butyric ester, back flow reaction is 26 hours again, with the solution heat filtering that obtains concentrate the thick product of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide;
(d) above-mentioned thick product is dissolved in the 100ml water, handles, collect the product part through 001 * 7 strongly acidic styrene type cation exchange resin 800ml.With in 201 * 7 strong-basicity styrene series anion exchange resins with collect the aqueous solution obtain, measure according to the pH of solution and reach at 7.0 ± 0.1 o'clock and judge neutralization and accomplish.
(e) solution concentration is collected in above-mentioned neutralization and do, add ethanol 150ml and heat, dissolve limpid back and add activated carbon 1g decolouring 30 minutes, filter, get white crystals product (S)-oxiracetam 18.6g behind the crystallisation by cooling; (volume ratio: 1/3) the mixed solvent recrystallization gets (S)-oxiracetam 12.3g (HPLC:99.34%) to adopt methanol/acetone again.
Analyze: test 1 is identical with the raw material and the consumption of test 2, and process step is basic identical, and what test 1 that different is was adopted is that gradation adds yellow soda ash, and the scope of control pH value is 8.0 ± 0.5; What adopt is once to add yellow soda ash and test 2, does not control the pH value scope, and measured pH value is 9.
Test 1 obtains finished product (S)-oxiracetam with test 2 and is respectively 19.0g (HPLC:99.14%) and 12.3g (HPLC:99.34%); Test 1 (S)-oxiracetam of obtaining manys 6.7g than testing 2 (S)-oxiracetams of obtaining, and purity only differs 0.2%.
Conclusion: destroy (S)-oxiracetam in the strong alkali solution easily, greatly the yield of influence (S)-oxiracetam.
Simultaneous test two: temperature of reaction is to the influence of (S)-oxiracetam yield
Test 3: the preparation method of a kind of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide, its concrete steps are:
(a) glycyl amide hydrochloride 55.0g, yellow soda ash 29.2g and absolute ethyl alcohol 500ml are dropped in the reaction flask, control pH value is about 7.4, is warming up to 60 ℃ under stirring;
(b) stirring progressively dripped (S)-4-chloro-ethyl 3-hydroxybutanoate 99.6g later in 2 hours, in the process that drips, divided 6 batches to add remaining yellow soda ash 29.1g, controlled the alkali number that at every turn adds through the inspection of pH value, to guarantee said reaction pH value≤8.5;
(c) after dripping (S)-4-halogen-3-butyric ester, back flow reaction is 26 hours again, with the solution heat filtering that obtains concentrate the thick product of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide;
(d) above-mentioned thick product is dissolved in the 100ml water, handles, collect the product part through 001 * 7 strongly acidic styrene type cation exchange resin 800ml.With in 201 * 7 strong-basicity styrene series anion exchange resins with collect the aqueous solution obtain, measure according to the pH of solution and reach at 7.0 ± 0.1 o'clock and judge neutralization and accomplish.
(e) solution concentration is collected in above-mentioned neutralization and do, add ethanol 150ml and heat, dissolve limpid back and add activated carbon 1g decolouring 30 minutes, filter, get white crystals product (S)-oxiracetam 18.8g behind the crystallisation by cooling; (volume ratio: 1/3) the mixed solvent recrystallization gets (S)-oxiracetam 12.5g (HPLC:99.35%) to adopt methanol/acetone again.
Adopt the test 1 in the simultaneous test one to organize as a comparison.
Analyze: test 1 is identical with the raw material and the consumption of test 3, and process step is basic identical, and the reaction of test 1 that different is is to carry out being warming up under the state of backflow; And test 3 temperature of reaction is 60 ℃, does not reach the temperature of solvent refluxing.
Test 1 obtains finished product (S)-oxiracetam with test 3 and is respectively 19.0g (HPLC:99.14%) and 12.5g (HPLC:99.35%); Test 1 (S)-oxiracetam of obtaining manys 6.5g than testing 3 (S)-oxiracetams of obtaining, and purity only differs 0.21%.
Conclusion: help sufficient reacting under the condition of backflow and carry out, can improve the yield of product (S)-oxiracetam greatly.
Beneficial effect of the present invention is:
1, the inventor is in the present invention through a large amount of tests repeatedly; Best pH value≤8.5 of the alkaline condition of having confirmed to react among the present invention, and can satisfy the required alkaline condition of reaction in the present invention through adding the pH value in the strict control of the alkali entire reaction course in batches, making; Feasible reaction can be carried out fully; Can avoid target product (S)-oxiracetam in strong base solution, to be destroyed again, thereby improve the yield of target product (S)-oxiracetam, reduce cost.
2, the inventor is controlled at temperature of reaction under the reflux state and carries out in the present invention, make reaction can be very fully, fully carry out, improved the yield of title product (S)-oxiracetam, reduced cost.
3, the present invention has adopted ion exchange resin treatment in purifying the finished product (S)-oxiracetam, compares with the available technology adopting silica gel column chromatography method, though treatment effect is suitable; But the on the one hand ion exchange resin repeated use of can repeatedly regenerating has reduced cost; Ion exchange resin is to use pure water to come wash-out on the other hand; Avoided with an organic solvent, pollution-free, simultaneously preferablyly be used for the big production of large-scale industrial.
4, the main raw material of the present invention's use is (S)-4-halogen-3-butyric ester and glycyl amide hydrochloride, is the commercial goods, the cheap and easy to get and environmental protection, pollution-free of raw material; The preparation feedback cycle among the present invention is short, and is easy and simple to handle, (S)-oxiracetam product of preparation, and its HPLC purity is up to more than 98.5%.
5, the most of organic solvent toxicity that uses among the present invention is little, pollution is low, and like ethanol, Virahol etc., it is avirulent that the water that uses in the last handling process is pollution-free especially, so the present invention not only is suitable for suitability for industrialized production, also meets national requirements for environmental protection.
In a word, the invention provides the method for preparing high purity (S)-oxiracetam that a kind of cost is low, yield is high and suitability for industrialized is produced.
Embodiment
Can further be well understood to the present invention through specific embodiment of the present invention given below, but they not to qualification of the present invention.
Embodiment 1
The preparation method of a kind of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide, its concrete steps are:
(a) glycyl amide hydrochloride 518.4g, sodium hydrogencarbonate 394g and absolute ethyl alcohol 3.7L are dropped in three mouthfuls of reaction flasks, control pH value is about 7.4, is warming up to backflow under stirring;
(b) backflow progressively dripped (S)-4-chloro-ethyl 3-hydroxybutanoate 781.6g later in 2 hours, in the process that drips, divided 8 batches to add remaining sodium hydrogencarbonate 394g, controlled the alkali number that at every turn adds through the inspection of pH value, to guarantee said reaction pH value≤8.5;
(c) after dripping (S)-4-halogen-3-butyric ester; Back flow reaction is 24 hours again; It is 75% o'clock termination reaction that HPLC measures product (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide content, with the solution heat filtering that obtains concentrate the thick product of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide;
(d) above-mentioned thick product is dissolved in the 800ml water, handles, collect the product part through 001 * 7 strongly acidic styrene type cation exchange resin 8.0L.With in 201 * 7 strong-basicity styrene series anion exchange resins with collect the aqueous solution obtain, measure according to the pH of solution and reach at 7.0 ± 0.1 o'clock and judge neutralization and accomplish.
(e) solution concentration is collected in above-mentioned neutralization and do, add ethanol 750ml and heat, dissolve limpid back and add activated carbon 10g decolouring 30 minutes, filter, get white crystals product (S)-oxiracetam 240g behind the crystallisation by cooling; (volume ratio: 1/3) mixed solvent (360ml/1080ml) recrystallization gets (S)-oxiracetam 160g (HPLC:99.3%) to adopt methanol/acetone again.
Embodiment 2
The preparation method of a kind of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide, its concrete steps are:
(a) glycyl amide hydrochloride 28.50g, sodium hydrogencarbonate 20.65g and absolute ethyl alcohol 200ml are dropped in three mouthfuls of reaction flasks, control pH value is about 7.4, is warming up to backflow under stirring;
(b) backflow progressively dripped (S)-4-chloro-ethyl 3-hydroxybutanoate 39.08g later in 2 hours, in the process that drips, divided 5 batches to add remaining sodium hydrogencarbonate 20.65g, controlled the alkali number that at every turn adds through the inspection of pH value, to guarantee said reaction pH value≤8.5;
(c) after dripping (S)-4-halogen-3-butyric ester; Back flow reaction is 24 hours again; It is 74% o'clock termination reaction that HPLC measures product (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide content, with the solution heat filtering that obtains concentrate the thick product of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide;
(d) above-mentioned thick product is dissolved in the 50ml water, handles, collect the product part through 001 * 7 strongly acidic styrene type cation exchange resin 500ml.With in 201 * 7 strong-basicity styrene series anion exchange resins with collect the aqueous solution obtain, measure according to the pH of solution and reach at 7.0 ± 0.1 o'clock and judge neutralization and accomplish.
(e) solution concentration is collected in above-mentioned neutralization and do, add ethanol 45ml and heat, dissolve limpid back and add activated carbon 1g decolouring 30 minutes, filter, get white crystals product (S)-oxiracetam 12.6g behind the crystallisation by cooling; (volume ratio: 1/3) mixed solvent (20ml/60ml) recrystallization gets (S)-oxiracetam 8.0g (HPLC:99.04%) to adopt methanol/acetone again.
Embodiment 3
The preparation method of a kind of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide, its concrete steps are:
(a) glycyl amide hydrochloride 277.1g, sodium hydrogencarbonate 210.6g and absolute ethyl alcohol 2000ml are dropped in three mouthfuls of reaction flasks, control pH value is about 7.4, is warming up to backflow under stirring;
(b) backflow progressively dripped (S)-4-chloro-ethyl 3-hydroxybutanoate 417.8g later in 2 hours, in the process that drips, divided 8 batches to add remaining sodium hydrogencarbonate 210.6g, controlled the alkali number that at every turn adds through the inspection of pH value, to guarantee said reaction pH value≤8.5;
(c) after dripping (S)-4-halogen-3-butyric ester; Back flow reaction is 24 hours again; It is 72% o'clock termination reaction that HPLC measures product (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide content, with the solution heat filtering that obtains concentrate the thick product of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide;
(d) above-mentioned thick product is dissolved in the 50ml water, handles, collect the product part through 001 * 7 strongly acidic styrene type cation exchange resin 4L.With in 201 * 7 strong-basicity styrene series anion exchange resins with collect the aqueous solution obtain, measure according to the pH of solution and reach at 7.0 ± 0.1 o'clock and judge neutralization and accomplish.
(e) solution concentration is collected in above-mentioned neutralization and do, add ethanol 400ml and heat, dissolve limpid back and add activated carbon 5g decolouring 30 minutes, filter, get white crystals product (S)-oxiracetam 143.0g behind the crystallisation by cooling; Adopt 1300ml Virahol recrystallization to get (S)-oxiracetam 87.0g (HPLC:99.57%) again.
Embodiment 4～7:
The preparation method of a kind of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide, wherein each raw material consumption and processing parameter are seen table 1～table 4, all the other are with embodiment 1.
Each raw material consumption and processing parameter among table 1 embodiment 4～7
The classification of the mineral alkali among table 2 embodiment 4～7
| ? | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 |
| Mineral alkali | Yellow soda ash | Sodium hydrogencarbonate | Salt of wormwood | Salt of wormwood |
Solvent classification among table 3 embodiment 4～7
| ? | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 |
| Solvent | Methyl alcohol | Propyl alcohol | Butanols | Virahol |
The classification of (the S)-4-halogen-3-butyric ester among table 4 embodiment 4～7
| ? | (S)-4-halogen-3-butyric ester |
| Embodiment 4 | (S)-4-chloro-3-beta-hydroxymethyl butyrate |
| Embodiment 5 | (S)-4-chloro-ethyl 3-hydroxybutanoate |
| Embodiment 6 | (S)-4-bromo-3-beta-hydroxymethyl butyrate |
| Embodiment 7 | (S)-4-bromo-ethyl 3-hydroxybutanoate |
Claims (6)
1. the preparation method of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide; It comprises that usefulness (S)-4-halogen-3-butyric ester and G-NH2 or glycyl amide hydrochloride are that raw material reacts the thick product and this thick purification of product that obtains (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide under alcoholic solvent and alkaline condition, is characterized in that: said alkaline condition reaction down is to add mineral alkali to control pH value≤8.5 in the said reaction through gradation in said reaction process; Said reaction is to carry out being warming up under the condition of backflow; Said purification process be with thick product with water dissolution after through strongly acidic cationic exchange resin and collect; Pass through in the strongly basic anion exchange resin again and the solution of collecting; Accomplish when the pH value that makes the solution of said collection is neutral, the thick product after the solution concentration of collecting that will neutralize then carries out recrystallization to be handled; Wherein said (S)-4-halogen-3-butyric ester, its structural formula is:
Wherein X represents halogen atom Br or Cl, and R represents the alkyl of 1～2 carbon atom,
Said alcoholic solvent be in methyl alcohol, ethanol, propyl alcohol, butanols and the Virahol any one or multiple, said mineral alkali is yellow soda ash, sodium hydrogencarbonate or salt of wormwood; Wherein the mol ratio of raw material (S)-4-halogen-3-butyric ester and glycyl amide hydrochloride is 1.0:0.8～1.2; (S)-and the amount ratio of 4-halogen-3-butyric ester and alcoholic solvent is 1 mole: 600～1000 milliliters; Said strongly acidic cationic exchange resin is: 001 * 7 strongly acidic styrene type cation exchange resin; Said strongly basic anion exchange resin is: 201 * 7 basicity styrene series anion exchange resins.
2. like the preparation method of each described (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide of claim 1; Wherein said recrystallization is handled; Promptly adopt ethanol to carry out the recrystallization processing first time, adopt the mixed solvent of Virahol or methanol/acetone to carry out the recrystallization processing second time.
3. the preparation method of (S)-4-hydroxyl as claimed in claim 2-2-OXo-1-pyrrolidine ethanamide in the wherein said first time recrystallization, adds activated carbon decolorizing to the thick product after said the concentrating.
4. the preparation method of (S)-4-hydroxyl as claimed in claim 3-2-OXo-1-pyrrolidine ethanamide, the weight ratio of the thick product after wherein said gac and said the concentrating is 1:30～80.
5. the preparation method of (S)-4-hydroxyl as claimed in claim 4-2-OXo-1-pyrrolidine ethanamide, it comprises following steps:
(a) glycyl amide hydrochloride and part mineral alkali are added in the alcoholic solvent, the consumption of mineral alkali is 7.3 ± 0.3 with control pH value, is warming up to backflow under stirring;
(b) progressively drip (S)-4-halogen-3-butyric ester, in the process that drips, add remaining mineral alkali again, in batches to control said reaction pH value≤8.5;
(c) drip (S)-4-halogen-3-butyric ester continued back flow reaction, reaction accomplish after-filtration concentrate the thick product of (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide;
(d) aqueous solution with above-mentioned thick product passes through also to collect behind the strongly acidic cationic exchange resin, passes through in the strongly basic anion exchange resin again and the solution of collection;
(e) handle carrying out first time recrystallization with ethanol after the solution concentration after the above-mentioned neutralization, must said product after carrying out recrystallization second time with the mixed solvent of Virahol or methanol/acetone.
6. the preparation method of (S)-4-hydroxyl as claimed in claim 5-2-OXo-1-pyrrolidine ethanamide, wherein a) in the step: said backflow is no less than 2 hours; (b) in the step: the said mineral alkali that in batches adds is 5～8 batches; (c) in the step: the said reaction times is 20～28 hours, the said heat filtering that is filtered into; (d) in the step: the aqueous solution of said thick product is pressed thick product: water=1 gram: 0.5～1.2 milliliter, the consumption of said strongly acidic cationic exchange resin is: said thick product: said strongly acidic cationic exchange resin=1 gram: 8～12 milliliters; (e) in the step, the consumption that said use ethanol carries out recrystallization processing for the first time is: the thick product after said the concentrating: ethanol=1 gram: 1.0～3.0 milliliters; The consumption of said second time of recrystallization in handling is: the thick product behind the recrystallization for the first time: Virahol=1 gram: 8.0～15.0 milliliters; Or the thick product behind the recrystallization for the first time: methyl alcohol=1 gram: 1.0～2.0 milliliters, wherein the volume ratio of methyl alcohol and acetone is 1:2～4 in the mixed solvent of methanol/acetone.
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Citations (3)
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|---|---|---|---|---|
| EP0223328A1 (en) * | 1985-07-26 | 1987-05-27 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| US5276164A (en) * | 1990-06-26 | 1994-01-04 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide |
| CN1956953A (en) * | 2004-05-25 | 2007-05-02 | 安国药品株式会社 | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0223328A1 (en) * | 1985-07-26 | 1987-05-27 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| US5276164A (en) * | 1990-06-26 | 1994-01-04 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide |
| CN1956953A (en) * | 2004-05-25 | 2007-05-02 | 安国药品株式会社 | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
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