CN109748837B - Preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide - Google Patents
Preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide Download PDFInfo
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- CN109748837B CN109748837B CN201810457021.4A CN201810457021A CN109748837B CN 109748837 B CN109748837 B CN 109748837B CN 201810457021 A CN201810457021 A CN 201810457021A CN 109748837 B CN109748837 B CN 109748837B
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Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide. The 4-hydroxy-2-oxo-1-pyrrolidine acetamide provided by the invention is prepared by intramolecular dehydration of 4-hydroxy-2-oxo-1-pyrrolidine acetic acid to obtain lactone, and the lactone is reacted with ammonia water to generate the lactone. The preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide provided by the invention has the advantages of short reaction period, mild conditions, low production cost, high product yield, good quality and the like, and is suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide.
Background
The invention relates to synthesis of 4-hydroxy-2-oxo-1-pyrrolidine acetamide (oxiracetam). The molecular formula of oxiracetam is C6H10N2O3The derivative is a synthesized hydroxyl aminobutyric acid cyclic derivative, and the structural formula is as follows:
oxiracetam is an intelligence-developing medicine acting on cholinergic brain stem network structures, is used for treating brain injury and induced neurological deficit, memory and intelligence disorder, and has wide market prospect.
According to the reports of the existing documents, the synthetic methods of oxiracetam mainly comprise the following methods:
japanese patent application JP53101367 discloses that 4-amino-3-hydroxybutyric acid is used as a starting material, and the target product is obtained through steps of hydroxyl protection, cyclization, substitution with ethyl 2-bromoacetate, deprotection and re-ammonolysis. The disadvantages of the route are that the raw materials and the amino protective agent are expensive, the production cost is high, and the route is not suitable for industrial production.
Chinese patent application CN1956953A discloses that oxiracetam is obtained by using chloroethylene oxide as an initial raw material through 5 steps of substitution, ring opening, hydrolysis, esterification and ring closing. Although the cost of raw materials of the route is not high, the method needs to use highly toxic cyanide and has many side reactions, so that not only is the intermediate difficult to purify, but also the final product needs ion exchange resin to remove salt, and the total yield is only 25-30%.
Chinese patent application CN1513836A discloses a process for preparing oxiracetam, which comprises using 4-haloacetoacetic acid derivative as starting material, reacting with azide of alkali metal or alkaline earth metal to obtain 4-azidoacetoacetic acid derivative, hydrogenating, cyclizing, ammoniating to obtain oxiracetam, wherein the route is as follows:
although the starting materials of the 4-hydroxy-2-oxo-1-pyrrolidine acetamide synthesized by the prior art are different, the defects of great safety risk of using part of the raw materials, complicated reaction steps, low total yield and poor product quality exist.
Therefore, the synthesis method of the 4-hydroxy-2-oxo-1-pyrrolidine acetamide, which has the advantages of short reaction period, mild reaction conditions, low production cost, high product yield and good quality and is suitable for industrial large-scale production, is developed.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing 4-hydroxy-2-oxo-1-pyrrolidineacetamide, which has a short reaction period and mild reaction conditions.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the 4-hydroxy-2-oxo-1-pyrrolidine acetamide is prepared by dehydrating 4-hydroxy-2-oxo-1-pyrrolidine in acetic acid molecule, and the lactone is generated by aminolysis reaction, and the reaction formula is as follows:
as a preferred embodiment, the preparation method of the present invention comprises the following steps:
1) mixing 4-hydroxy-2-oxo-1-pyrrolidine acetic acid with an aprotic solvent, and carrying out heat preservation reaction to obtain lactone;
2) dissolving the lactone obtained in the step 1) in a polar organic solvent, adding the dissolved lactone into ammonia water, and reacting to obtain 4-hydroxy-2-oxo-1-pyrrolidine acetamide.
Preferably, in step 1), the aprotic solvent is selected from one or more of N, N-Dimethylformamide (DMF), N-dimethylacetamide (dme), Dimethylsulfoxide (DMSO), acetonitrile.
Preferably, in step 1), the mass ratio of the aprotic solvent to 4-hydroxy-2-oxo-1-pyrrolidineacetic acid is 0.4 to 0.8: 1. further, it is preferably 0.5 to 0.6: 1.
preferably, in the step 1), the reaction temperature of the 4-hydroxy-2-oxo-1-pyrrolidine acetic acid is 100-160 ℃, preferably 120-140 ℃. Further, it is preferably 130-140 ℃.
Preferably, in the step 1), the reaction time of the 4-hydroxy-2-oxo-1-pyrrolidine acetic acid is 1.5-2 h.
Preferably, after the heat preservation reaction in the step 1), cooling, adding the reaction system into water for pulping, and performing suction filtration to obtain the lactone.
Further, the temperature after temperature reduction is 100-.
Preferably, in step 2), the polar organic solvent is one or more of methanol, ethanol, n-propanol, isopropanol and tert-butanol.
Preferably, in the step 2), the ammonia water refers to an aqueous solution containing 25-28% of ammonia by mass.
Further, the mass of the ammonia water is 4-5 times of that of the lactone.
Preferably, in step 2), the reaction temperature is 20-25 ℃.
Preferably, in step 2), the reaction time is 10-12 h.
Preferably, after step 2), the 4-hydroxy-2-oxo-1-pyrrolidineacetamide is precipitated and recrystallized.
Further, the process of precipitating and recrystallizing 4-hydroxy-2-oxo-1-pyrrolidine acetamide is as follows: evaporating the solvent to dryness, adding acetone for crystallization to obtain a crude product, and recrystallizing with methanol to obtain a high-purity target product, namely 4-hydroxy-2-oxo-1-pyrrolidine acetamide.
The synthesis method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide provided by the invention has the advantages of short reaction period, mild reaction conditions and low production cost, and is suitable for industrial large-scale production.
The second purpose of the invention is to provide 4-hydroxy-2-oxo-1-pyrrolidine acetamide prepared by the method of the first purpose.
In order to achieve the purpose, the technical scheme of the invention is as follows:
according to the preparation method of the object one, 4-hydroxy-2-oxo-1-pyrrolidine acetamide is prepared.
According to the preparation method of the invention, the molar yield of the 4-hydroxy-2-oxo-1-pyrrolidine acetamide in the prepared product reaches more than 80 percent, and the purity reaches 99.9 percent. The product of the invention has high yield and good quality.
The invention has the beneficial effects that: the invention provides a synthesis method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide, which comprises the following steps:
1) short reaction period, mild reaction conditions, low production cost and suitability for industrial large-scale production.
2) The product of the invention has high yield and good quality, the yield reaches more than 80 percent, and the purity reaches 99.9 percent.
Detailed Description
Hereinafter, preferred embodiments of the present invention will be described in detail. The experimental methods of the preferred embodiments, which do not indicate specific conditions, are generally performed according to conventional conditions, and the examples are given for better illustration of the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
Example 1
(1) Mixing 10g of 4-hydroxy-2-oxo-1-pyrrolidine acetic acid (the same as that in the pharmaceutical and technology Limited of Yangxin, Hubei) with 5g of DMF, heating to dissolve the mixture, keeping the temperature at 130 ℃ and 135 ℃ for reaction for 2h, cooling to 100 ℃, adding the mixture into 40g of water for pulping, and performing suction filtration to obtain 9.5g of wet lactone.
(2) Dissolving 9.5g lactone with 5g methanol, adding into 40g 25% (mass fraction of ammonia, the same below) ammonia water, keeping the temperature at 20-25 ℃ for reaction for 12h, evaporating the solvent, adding 20g acetone, crystallizing to obtain 8.90g crude product, recrystallizing with methanol, and drying to obtain 8.2g target product: the molar yield of 4-hydroxy-2-oxo-1-pyrrolidine acetamide is 82.6%, and the HPLC purity is 99.9%.
Example 2
(1) Mixing 10g of 4-hydroxy-2-oxo-1-pyrrolidine acetic acid with 5g of DMSO, heating to dissolve the mixture while stirring, keeping the temperature at 130 ℃ and 135 ℃ for reaction for 2h, cooling to 102 ℃ after the reaction is finished, adding the mixture into 40g of water for pulping, and performing suction filtration to obtain 9.4g of lactone wet weight.
(2) Dissolving 9.4g of lactone wet product with 5g of ethanol, adding the dissolved lactone wet product into 46g of 25% ammonia water, keeping the temperature at 20-25 ℃ for reaction for 12 hours, evaporating the solvent to dryness, adding 15g of acetone for crystallization to obtain a crude product, and recrystallizing with methanol to obtain 8.1g of a target product, wherein the molar yield is 81.5%, and the HPLC purity is 99.9%.
Example 3
(1) Mixing 20g of 4-hydroxy-2-oxo-1-pyrrolidine acetic acid with 10g of DMF, heating to dissolve and clear under stirring, keeping the temperature at 130 ℃ and 135 ℃ for reaction for 2h, cooling to 100 ℃, adding the mixture into 80g of water for pulping after the reaction is finished, and performing suction filtration to obtain 19.8g of lactone wet weight.
(2) Dissolving the wet lactone product with 5g of methanol, adding the dissolved lactone product into 100g of 25% ammonia water, keeping the temperature at 20-25 ℃ for reaction for 13h, evaporating the solvent to dryness, adding 30g of acetone for crystallization to obtain a crude product, and recrystallizing with methanol to obtain 8.13g of a target product, namely 4-hydroxy-2-oxo-1-pyrrolidine acetamide, wherein the molar yield is 81.8%, and the HPLC purity is 99.9%.
The product of example 1 was analyzed by nmr spectroscopy, and the results were as follows:
1H-NMR(300MHz，DMSO-d6)δ2.10(d，1H),2.57(dd，1H),3.69(d，1H),3.88(d，1H),4.10(d，1H),4.31(m，1H),5.25(s，1H),7.13(s，1H),7.33(s，1H)。
attached: the HPLC method for determining the purity of 4-hydroxy-2-oxo-1-pyrrolidine acetamide comprises the following steps:
1. the instrument comprises the following steps: high performance liquid chromatograph
2. Reagents and solutions
Acetonitrile (HPLC), potassium dihydrogen phosphate (AR), phosphoric Acid (AR), ammonia water (AR);
preparation of a mobile phase: phosphate buffer solution (taking 4.08g of monopotassium phosphate, adding 500ml of water for dissolving, adding 5ml of ammonia water with the mass fraction of 25-28%, adding water for diluting to 1000ml, uniformly mixing, adjusting the pH value to 3.5 +/-0.1 by using phosphoric acid) -acetonitrile (the volume ratio is 26:74) as a mobile phase, and filtering and degassing for later use.
Preparing a test solution: weighing 50mg of sample into a 25ml measuring flask, adding the mobile phase for dissolving and diluting to the scale, and shaking up.
3. Chromatographic conditions and system adaptability experiment: amino bonded silica gel is used as a filling agent, phosphate buffer solution-acetonitrile (volume ratio is 26:74) is used as a mobile phase, the flow rate is 1.0ml/min, and the detection wavelength is 210 nm.
4. The determination step comprises: injecting equal volume (20ul) of blank solvent and sample solution into high performance liquid chromatograph, and recording chromatogram for 30 min. The chromatographic purity was calculated by area normalization with the blank solvent subtracted.
Therefore, the product prepared by the method has high yield, high purity and good quality. The method for preparing 4-hydroxy-2-oxo-1-pyrrolidine acetamide uses 4-hydroxy-2-oxo-1-pyrrolidine acetic acid as a starting material to form lactone, and then aminolysis is carried out to obtain a high-purity target product. The method has the advantages of short reaction period, mild reaction conditions and low production cost, and is suitable for industrial mass production.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (10)
1. The preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide is characterized in that 4-hydroxy-2-oxo-1-pyrrolidine acetamide is prepared by intramolecular dehydration of 4-hydroxy-2-oxo-1-pyrrolidine acetic acid to obtain lactone, and the lactone is subjected to ammonolysis reaction to generate the product, wherein the reaction formula is as follows:
2. the method of claim 1, comprising the steps of:
1) mixing 4-hydroxy-2-oxo-1-pyrrolidine acetic acid with an aprotic solvent, and carrying out heat preservation reaction to obtain lactone;
2) dissolving the lactone obtained in the step 1) in a polar organic solvent, adding the dissolved lactone into ammonia water, and reacting to obtain 4-hydroxy-2-oxo-1-pyrrolidine acetamide.
3. The method according to claim 2, wherein the aprotic solvent is one or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, and acetonitrile in step 1).
4. The method according to claim 2, wherein the mass ratio of the aprotic solvent to 4-hydroxy-2-oxo-1-pyrrolidineacetic acid in step 1) is 0.4 to 0.8: 1.
5. the method as claimed in claim 2, wherein the reaction temperature of the 4-hydroxy-2-oxo-1-pyrrolidineacetic acid in the step 1) is 100-160 ℃.
6. The method as claimed in claim 2, wherein the reaction temperature of the 4-hydroxy-2-oxo-1-pyrrolidineacetic acid in the step 1) is 130-140 ℃.
7. The preparation method according to claim 2, wherein the lactone is obtained by cooling after the heat preservation reaction in step 1), adding the reaction system into water for pulping and performing suction filtration.
8. The method according to claim 2, wherein the polar organic solvent in step 2) is one or more selected from methanol, ethanol, n-propanol, isopropanol and tert-butanol.
9. The method according to claim 2, wherein the aqueous ammonia solution in the step 2) is an aqueous solution containing 25 to 28 mass% of ammonia.
10. The process according to claim 2, wherein the product is precipitated after the step 2) and recrystallized from methanol to obtain 4-hydroxy-2-oxo-1-pyrrolidineacetamide.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058911A (en) * | 2011-10-19 | 2013-04-24 | 重庆福安药业(集团)股份有限公司 | Oxiracetam preparation technology |
| CN106496089A (en) * | 2016-02-05 | 2017-03-15 | 华润双鹤药业股份有限公司 | A kind of method for preparing Oxiracetam |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058911A (en) * | 2011-10-19 | 2013-04-24 | 重庆福安药业(集团)股份有限公司 | Oxiracetam preparation technology |
| CN106496089A (en) * | 2016-02-05 | 2017-03-15 | 华润双鹤药业股份有限公司 | A kind of method for preparing Oxiracetam |
Non-Patent Citations (2)
| Title |
|---|
| Stereoselective synthesis of a dialkylhydantoin featuring an asymmetric Strecker reaction on an acyclic dialkyl ketone;Neil Barnwell，et al.;《Tetrahedron Letters》;20120210;第53卷;1951-1953 * |
| Synthesis of mustards from putrescine，cadaverine，and 1,3-diaminopropane;William W.Lee，et al.;《Journal of Medicinal Chemistry》;19630930;第6卷(第5期);567-569 * |
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