CN114621128A - Preparation method of (S) -oxiracetam - Google Patents
Preparation method of (S) -oxiracetam Download PDFInfo
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- CN114621128A CN114621128A CN202210240105.9A CN202210240105A CN114621128A CN 114621128 A CN114621128 A CN 114621128A CN 202210240105 A CN202210240105 A CN 202210240105A CN 114621128 A CN114621128 A CN 114621128A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
Abstract
The invention discloses a preparation method of (S) -oxiracetam, which comprises the following steps: s1, condensing S-4-chloro-3-hydroxybutyric acid ethyl ester serving as an initial raw material with glycinamide under an alkaline condition to obtain a crude reaction liquid containing a product (S) -oxiracetam; s2, reacting the crude reaction solution obtained in the step S1 with a protective reagent to obtain an intermediate I, wherein the protective reagent is methyl tert-butyl chlorosilane; s3, crystallizing and purifying the intermediate I obtained in the step S2 in a first solvent to obtain a high-purity intermediate I; s4, reacting the high-purity intermediate I obtained in the step S3 with an acid catalyst in a second solvent to obtain the high-purity (S) -oxiracetam. The (S) -oxiracetam prepared by the preparation method has high product purity and chiral purity, and does not need column chromatography purification.
Description
Technical Field
The invention relates to the technical field of preparation of (S) -oxiracetam, in particular to a preparation method of (S) -oxiracetam.
Background
Oxiracetam was the first nootropic drug synthesized in 1974 by steckebechmm, italy and is a racemate consisting of two isomers, (S) -oxiracetam ((S) -oxiracetam) and (R) -oxiracetam ((R) -oxiracetam). (S) -oxiracetam is a single enantiomer of oxiracetam with the chemical name: (S) -4-hydroxy-2 oxo-1-pyrrolidineacetamide. Oxiracetam, a nootropic drug, is a synthetic derivative of hydroxyaminobutanoic acid (GABOB), which is a central nervous system drug that can promote learning, enhance memory, and protect damaged nerve cells.
At present, (S) -oxiracetam is produced mainly by reacting (S) -4-chloro-3-hydroxybutanoic acid ethyl ester with glycinamide to obtain a target compound, or reacting with glycinate ethyl ester, and then performing ammonolysis to obtain the target compound. The (S) -4-chloro-3-hydroxybutyrate reacts with the glycinamide under the alkaline condition to obtain the final product (S) -oxiracetam, wherein the alkalinity of a reaction liquid is controlled by adding alkali at one time, but as the raw materials (S) -4-chloro-3-hydroxybutyrate ethyl ester and oxiracetam are easy to damage in a strong alkali solution, a plurality of side reactions are generated, so that the reaction is low in purity and has a plurality of impurities, and as the (S) -oxiracetam has strong hydrophilicity, the product is difficult to purify, the obtained product is difficult to separate from impurity salt compounds generated by various reactions, and the generated impurity salts are removed by column chromatography to further carry out crystallization and purification.
The column chromatography is not only costly, but also cumbersome to operate, for example: performing silica gel column chromatography with dichloromethane-methanol mixed solvent as eluent, concentrating the obtained effluent, removing solvent, and recrystallizing with methanol to obtain the product. However, silica gel column chromatography is very complicated in operation, needs a large amount of organic solvents, and is high in cost and difficult to industrialize. For another example: the purification method comprises the steps of performing column chromatography on the strongly acidic cation exchange resin, neutralizing the strongly basic anion exchange resin with No. 711, collecting effluent, concentrating the effluent, and crystallizing the effluent by using ethanol to obtain the product. Therefore, the separation, purification and refinement of (S) -oxiracetam are always the most central difficulties of the product.
Disclosure of Invention
The invention aims to provide a preparation method of (S) -oxiracetam, and the (S) -oxiracetam prepared by the preparation method has high product purity and chiral purity, and does not need column chromatography purification.
The invention is realized by the following technical scheme:
a preparation method of (S) -oxiracetam, comprising the following steps:
s1, condensing S-4-chloro-3-hydroxybutyric acid ethyl ester serving as an initial raw material with glycinamide under an alkaline condition to obtain a crude reaction liquid containing a product (S) -oxiracetam;
s2, reacting the crude reaction solution obtained in the step S1 with a protective reagent to obtain an intermediate I, wherein the protective reagent is methyl tert-butyl chlorosilane;
s3, crystallizing and purifying the intermediate I obtained in the step S2 in a first solvent to obtain a high-purity intermediate I;
s4, reacting the high-purity intermediate I obtained in the step S3 with an acid catalyst in a second solvent to obtain the high-purity (S) -oxiracetam.
The reaction process of the invention is as follows:
the S-oxiracetam is a compound with strong hydrophilicity, is extremely difficult to separate from various large-polarity salt compounds used in the preparation process and generated by reaction, such as glycinamide, sodium bicarbonate, ammonium chloride and the like, and cannot be crystallized smoothly before the salt compounds are removed.
The applicant finds out through experiments that:
the hydroxyl group in the structure of S-oxiracetam is an important group for keeping the large polarity and the hydrophilicity of the S-oxiracetam, shielding the hydroxyl group in a protective group connection mode can reduce the polarity of the hydroxyl group to a great extent, so that the property of the hydroxyl group is converted from strong hydrophilicity to hydrophobicity, the reaction is simple to operate and low in cost, the connected compound can easily remove the large polar salt compound which is difficult to remove only by simple organic solvent and water extraction washing, and the crystallinity of the S-oxiracetam can be enhanced after the S-oxiracetam is connected with part of protecting groups, so that the S-oxiracetam is easier to crystallize and precipitate, therefore, an important intermediate capable of being crystallized and purified is added, the crystallization and purification difficulty of the product is reduced, the scheme that the qualified product can be obtained only by repeated crystallization and purification after the traditional column chromatography is changed into the scheme that the high-purity product can be obtained only by simple recrystallization after the protective group is removed.
In the course of further experiments, the applicant tried a plurality of protecting groups (protecting reagents), and the following conditions need to be satisfied in terms of protecting group selection:
1) the protecting group reagent is cheap and easy to obtain;
2) the connection between the protecting group and the S-oxiracetam and the removal operation of the protecting group are simple and the yield is high;
3) the polarity of the intermediate after the protecting group is connected with the S-oxiracetam is moderate, and the salt compound generated by the reaction can be easily removed by using an organic solvent and water for extraction and washing;
4) after the protecting groups are connected, the crystallinity of the intermediate can be enhanced, so that the connected intermediate can be well crystallized and purified.
The dimethyl tert-butyl silane protecting group is a preferable protecting group, dimethyl tert-butyl chlorosilane serving as a raw material is a bulk commodity and is low in price, the conversion rate of connection and removal of the dimethyl tert-butyl chlorosilane and S-oxiracetam is over 95%, the polarity of a connected intermediate is moderate, salt impurities can be removed by simple water extraction and washing, the crystallinity is excellent, the crystallization loss is low, most impurities can be completely removed in the intermediate crystal, the purity of a simple once-crystallization liquid phase is over 99.5%, and the purity of a product obtained after the protecting group is removed can be over 99.9% through a once-simple recrystallization liquid phase.
A comparison experiment is carried out on the crude product mother liquor with the same content by using the traditional ion exchange resin column chromatography scheme and the scheme of the application, and the final yield of the obtained qualified product is improved by 30-50% compared with the traditional scheme, and the production cost is reduced by 30-50%.
In conclusion, the preparation method disclosed by the invention has the advantages that the protective reagent is added into the crude reaction liquid containing the product (S) -oxiracetam to protect the hydroxyl in the S) -oxiracetam, so that the by-product of the reaction in the step S1 can be removed in the subsequent crystallization and purification process, the high-purity intermediate I is obtained, the purity of the (S) -oxiracetam prepared from the intermediate I can reach more than 99.9%, and the optical purity can reach more than 99.9%.
Further, in step S1, the alkaline reagent used at least includes one of potassium carbonate, sodium carbonate and sodium bicarbonate.
Further, the specific process in step S2 is as follows:
concentrating the crude reaction liquid, dissolving the concentrated crude reaction liquid in a third solvent, and carrying out condensation reaction with a protective reagent under the condition of dripping an acid-binding agent, wherein the reaction temperature is 0-60 ℃; the reaction time is 1-10 hours.
Further, the molar ratio of the protecting reagent to the starting material is: 1:1 to 2.5.
Further, the third solvent comprises at least one of acetonitrile, isopropyl ether, toluene, ethyl acetate, DMF, DMSO, and N-methylpyrrolidone; the acid-binding agent at least comprises one of triethylamine, pyridine, lutidine, imidazole, piperidine, potassium carbonate and sodium bicarbonate.
Preferably; the third solvent is acetonitrile, ethyl acetate, DMF or DMSO.
Preferably; firstly, concentrating a reaction solution to be purified, reacting the reaction solution with a protective reagent with a molar ratio of 1: 1.5-1.65 (the actual amount of product oxiracetam in the reaction solution to be purified and the molar ratio between acid-binding agents) in the presence of an acid-binding agent for 1-3 hours to obtain a solution containing an intermediate I, and then collecting the intermediate I from the solution containing the intermediate I
Further, in step S3, the first solvent includes at least one of acetonitrile, isopropyl ether, toluene, ethyl acetate, n-hexane, water, acetone, and DMF.
Preferably, the first solvent is isopropyl ether, n-hexane, acetone, ethyl acetate or water
Further, in step S4, the molar ratio of the intermediate I to the acidic catalyst is: 1: 0.1-0.5.
Further, in step S4, the reaction temperature is 0-100 ℃ and the reaction time is 5-10 hours.
Further, in step S4, the acidic catalyst includes at least one of acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, and phosphoric acid.
Further, in step S4, the second solvent includes at least one of methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile, and dioxane.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. by the preparation method, the purity of the obtained (S) -oxiracetam can reach more than 99.9 percent, and the optical purity can reach more than 99.9 percent.
2. Compared with the prior art, the preparation method provided by the invention is simple to operate, does not need column chromatography, is low in cost and high in purity, and can realize industrial production.
3. The invention provides a new idea for preparing high-purity (S) -oxiracetam and has industrial guiding significance.
Drawings
The accompanying drawings, which are included to provide a further understanding of the embodiments of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the principles of the invention. In the drawings:
FIG. 1 is an HPLC chromatogram of intermediate I of example 1;
FIG. 2 is an HPLC chromatogram of the (S) -oxiracetam product of example 1;
FIG. 3 is an HPLC profile of intermediate I of example 2;
FIG. 4 is an HPLC chromatogram of the (S) -oxiracetam product of example 2.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples and accompanying drawings, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not meant to limit the present invention.
Example 1:
a preparation method of (S) -oxiracetam, comprising the following steps:
s1, preparation of crude reaction liquid containing the product (S) -oxiracetam:
dissolving 40g of S-4-chloro-3-hydroxybutanoic acid ethyl ester in 400ml of ethanol, adding 50g of glycinamide hydrochloride and 50g of anhydrous sodium carbonate, and refluxing and stirring for 24 hours to obtain a crude reaction solution containing the product (S) -oxiracetam;
s2, preparation of intermediate I:
concentrating the crude reaction liquid containing the product (S) -oxiracetam obtained in the step S1 to remove the solvent ethanol, dissolving the reaction liquid in 500ml of ethyl acetate, cooling to 0 ℃, adding 64g of triethylamine, stirring for 30 minutes, adding 55g of dimethyl tert-butyl chlorosilane, stirring for 5 hours at the same temperature after the dropwise addition is finished, adding 500ml of water, separating out an organic phase, and concentrating to obtain 30.5g of an intermediate I;
s3, preparation of high-purity intermediate I:
dissolving the intermediate I obtained in the step S2 in 300ml of isopropyl ether, heating to reflux and dissolve, cooling to 0 ℃, stirring, precipitating a large amount of solid, filtering, and drying to obtain 28g of a refined product of the intermediate I; purity 99.8% by HPLC;
s4, preparation of high-purity (S) -oxiracetam:
and (4) adding the refined intermediate I obtained in the step S3 into 200ml of dioxane, adding 5ml of concentrated hydrochloric acid, stirring for 5 hours at 100 ℃, separating out a large amount of solid, cooling to 0 ℃, crystallizing for 5 hours, and filtering to obtain 14.5g of a product, wherein the purity is 99.9% by HPLC (high performance liquid chromatography) detection, and the optical purity is 99.9%.
HPLC detection adopts TBS-S-ALXT detection:
and (3) chromatographic column: asahi AQ 18 column 250 × 4.6mm, 5 μm; λ 210 nm; t is 25 ℃; flow ═ 1.0 mL/min; inj ═ 20 μ L;
mobile phase: 95% ACN-10mM K2PO4 (containing 0.1% phosphoric acid) at 40:60 for 20 min;
sample preparation: 10mg of the sample was weighed and dissolved in 10mL of acetonitrile-water (50: 50).
The HPLC profile of the intermediate I in this example is shown in FIG. 1, and the HPLC profile of the (S) -oxiracetam product is shown in FIG. 2.
Example 2:
a preparation method of (S) -oxiracetam, comprising the following steps:
s1, preparation of a crude reaction solution containing the product (S) -oxiracetam:
dissolving 40g of S-4-chloro-3-hydroxybutanoic acid ethyl ester in 400ml of isopropanol, adding 50g of glycinamide hydrochloride and 38g of anhydrous sodium bicarbonate, and refluxing and stirring for 48 hours to obtain a crude reaction solution containing the product (S) -oxiracetam;
s2, preparation of intermediate I:
concentrating the crude reaction liquid containing the product (S) -oxiracetam obtained in the step S1 to remove the solvent isopropanol, dissolving the reaction liquid in 500ml of DMF, cooling to 10 ℃, adding 45g of imidazole, stirring for 30 minutes, adding 55g of dimethyl tert-butyl chlorosilane, stirring for 5 hours at the same temperature after the addition is finished, adding 500ml of water and 500ml of ethyl acetate, separating to separate an organic phase, and concentrating to obtain 30.2g of an intermediate I;
s3, preparation of high-purity intermediate I:
and (4) dissolving the intermediate I obtained in the step S2 in 300ml of normal hexane, heating to reflux and dissolve, cooling to 0 ℃, stirring, separating out a large amount of solids, filtering, and drying to obtain 28.6g of a refined product of the intermediate I. Purity 99.8% by HPLC;
s4, preparation of high-purity (S) -oxiracetam:
adding the refined intermediate I obtained in the step S3 into 200ml of isopropanol, adding 2ml of methanesulfonic acid, stirring for 5 hours at 80 ℃, separating out a large amount of solid, cooling to 0 ℃ for crystallization for 5 hours, and filtering to obtain 14.5g of a product with the purity of 99.9% and the optical purity of 99.9% by HPLC (high performance liquid chromatography).
The HPLC profile of the intermediate I in the example is shown in figure 3, and the HPLC profile of the (S) -oxiracetam product is shown in figure 4
Example 3:
a preparation method of (S) -oxiracetam comprises the following steps:
s1, preparation of a crude reaction solution containing the product (S) -oxiracetam:
dissolving 40g of S-4-chloro-3-hydroxybutanoic acid ethyl ester in 400ml of n-propanol, adding 50g of glycinamide hydrochloride and 66g of anhydrous potassium carbonate, and refluxing and stirring for 48 hours to obtain a crude reaction solution containing the product (S) -oxiracetam;
s2, preparation of intermediate I:
concentrating the crude reaction liquid containing the product (S) -oxiracetam obtained in the step S1 to remove a solvent n-propanol, dissolving the reaction liquid in 500ml of DMSO, cooling to 10 ℃, adding 52g of pyridine, stirring for 30 minutes, adding 55g of dimethyl tert-butyl chlorosilane, stirring for 5 hours at the same temperature after the addition is finished, adding 500ml of water and 500ml of ethyl acetate, separating to separate an organic phase, and concentrating to obtain 29.8g of an intermediate I;
s3, preparation of high-purity intermediate I:
and (4) dissolving the intermediate I obtained in the step S2 in 300ml of ethyl acetate, heating to reflux and dissolve, cooling to 0 ℃, stirring, precipitating a large amount of solid, filtering, and drying to obtain 28.4g of a refined product of the intermediate I. Purity 99.8% by HPLC;
s4, preparation of high-purity (S) -oxiracetam:
adding the refined intermediate I obtained in the step S3 into 200ml of acetone, adding 2ml of phosphoric acid, stirring for 5 hours at 50 ℃, separating out a large amount of solid, cooling to 0 ℃ for crystallization for 5 hours, and filtering to obtain 13.9g of a product with the purity of 99.9% and the optical purity of 99.9% by HPLC detection.
Example 4:
a preparation method of (S) -oxiracetam, comprising the following steps:
s1, preparation of crude reaction liquid containing the product (S) -oxiracetam:
dissolving 40g of S-4-chloro-3-hydroxybutyric acid ethyl ester in 400ml of ethanol, adding 50g of glycinamide hydrochloride and 66g of anhydrous potassium carbonate, and refluxing and stirring for 48 hours to obtain a crude reaction solution containing the product (S) -oxiracetam;
s2, preparation of intermediate I:
concentrating the crude reaction liquid containing the product (S) -oxiracetam obtained in the step S1 to remove the solvent ethanol, dissolving the crude reaction liquid in 500ml of acetonitrile, cooling to 10 ℃, adding 88g of potassium carbonate, stirring for 30 minutes, adding 55g of dimethyl tert-butyl chlorosilane, stirring for 5 hours at the same temperature after the addition is finished, adding 500ml of water and 500ml of ethyl acetate, separating to separate an organic phase, and concentrating to obtain an intermediate I29.8g;
s3, preparation of high-purity intermediate I:
and (4) dissolving the intermediate I obtained in the step S2 in 300ml of acetone, heating to reflux and dissolve, cooling to 0 ℃, stirring, precipitating a large amount of solid, filtering, and drying to obtain 28.1g of a refined product of the intermediate I. Purity 99.8% by HPLC;
s4, preparation of high-purity (S) -oxiracetam:
adding the refined intermediate I obtained in the step S3 into 200ml of ethanol, adding 2ml of acetic acid, stirring for 5 hours at 70 ℃, separating out a large amount of solid, cooling to 0 ℃ for crystallization for 5 hours, and filtering to obtain 14.1g of a product with the purity of 99.9% and the optical purity of 99.9% by HPLC detection.
Comparative example 1:
a preparation method of (S) -oxiracetam, comprising the following steps:
1) dissolving 40g of S-4-chloro-3-hydroxybutanoic acid ethyl ester in 400ml of ethanol, adding 50g of glycinamide hydrochloride and 66g of anhydrous potassium carbonate, and refluxing and stirring for 48 hours to obtain a crude reaction solution containing the product (S) -oxiracetam;
2) concentrating the obtained crude reaction liquid containing the product (S) -oxiracetam to remove the solvent ethanol, dissolving the crude reaction liquid in 500ml of acetonitrile, cooling to 10 ℃, adding 64g of triethylamine, stirring for 30 minutes, adding 70g of p-toluenesulfonyl chloride, stirring for 5 hours at the same temperature after the addition is finished, adding 500ml of water and 500ml of ethyl acetate, separating out an organic phase, and concentrating to obtain 15.1g of an intermediate;
3) and dissolving the obtained intermediate in 200ml of methanol containing 15% ammonia gas, stirring at room temperature for 15 hours, concentrating to remove the solvent, adding 200ml of ethanol, stirring and crystallizing to obtain 3.2g of a product with the liquid phase purity of 95.2%.
Namely, the biggest difference between the comparative example and the example is that:
different protective reagents, the protective reagent of this comparative example was tosyl chloride. From the data of comparative example 1, it is clear that the yield is low and the degree of purification of the product is not satisfactory, using tosyl chloride as protecting agent.
Comparative example 2:
a preparation method of (S) -oxiracetam, comprising the following steps:
1) dissolving 40g of S-4-chloro-3-hydroxybutanoic acid ethyl ester in 400ml of isopropanol, adding 50g of glycinamide hydrochloride and 50g of anhydrous sodium carbonate, and refluxing and stirring for 48 hours to obtain a crude reaction solution containing the product (S) -oxiracetam;
2) concentrating the obtained crude reaction liquid containing the product (S) -oxiracetam to remove the solvent isopropanol, dissolving in 500ml of DMF, cooling to 10 ℃, adding 64g of triethylamine, stirring for 30 minutes, adding 40g of acetic anhydride, stirring for 5 hours at the same temperature after the addition is finished, adding 500ml of water and 500ml of ethyl acetate, separating out an organic phase, and concentrating until no solid is separated out.
Namely, the biggest difference between the comparative example and the example is that:
different protective reagents, the protective reagent of the comparative example is acetic anhydride. From the data of comparative example 1, it can be seen that (S) -oxiracetam could not be prepared using acetic anhydride as a protecting agent.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A preparation method of (S) -oxiracetam is characterized by comprising the following steps:
s1, condensing S-4-chloro-3-hydroxybutyric acid ethyl ester serving as an initial raw material with glycinamide under an alkaline condition to obtain a crude reaction liquid containing a product (S) -oxiracetam;
s2, reacting the crude reaction solution obtained in the step S1 with a protective reagent to obtain an intermediate I, wherein the protective reagent is methyl tert-butyl chlorosilane;
s3, crystallizing and purifying the intermediate I obtained in the step S2 in a first solvent to obtain a high-purity intermediate I;
s4, reacting the high-purity intermediate I obtained in the step S3 with an acid catalyst in a second solvent to obtain the high-purity (S) -oxiracetam.
2. The method of claim 1, wherein the basic reagent used in step S1 comprises at least one of potassium carbonate, sodium carbonate and sodium bicarbonate.
3. The method for preparing (S) -oxiracetam according to claim 1, wherein the specific process in step S2 is as follows:
concentrating the crude reaction solution, dissolving the concentrated crude reaction solution in a third solvent, and performing condensation reaction with a protective reagent under the condition of dripping an acid-binding agent, wherein the reaction temperature is 0-60 ℃; the reaction time is 1-10 hours.
4. The preparation method of (S) -oxiracetam according to claim 3, wherein the molar ratio of the protecting reagent to the starting materials is as follows: 1:1 to 2.5.
5. The process of claim 3, wherein the third solvent comprises at least one of acetonitrile, isopropyl ether, toluene, ethyl acetate, DMF, DMSO, and N-methylpyrrolidone; the acid-binding agent at least comprises one of triethylamine, pyridine, lutidine, imidazole, piperidine, potassium carbonate and sodium bicarbonate.
6. The method of claim 1, wherein in step S3, the first solvent comprises at least one of acetonitrile, isopropyl ether, toluene, ethyl acetate, n-hexane, water, acetone, and DMF.
7. The method for preparing (S) -oxiracetam according to claim 1, wherein in the step S4, the molar ratio of the intermediate I to the acidic catalyst is as follows: 1: 0.1-0.5.
8. The method for preparing (S) -oxiracetam according to claim 1, wherein in step S4, the reaction temperature is 0-100 ℃ and the reaction time is 5-10 hours.
9. The method of claim 1, wherein in step S4, the acidic catalyst comprises at least one of acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, and phosphoric acid.
10. The method of claim 1, wherein the second solvent comprises at least one of methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile, and dioxane in step S4.
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