CN102603603A - Method for preparing (S)-oxiracetam - Google Patents

Abstract

A method for preparing (S)-oxiracetam, adopting glycine ethyl ester hydrochloride and (S)-4-halo-3-hydroxy-butyric acid ethyl ester as raw materials to react under alcohol solvent and alkaline conditions, Filter, wash the filtrate with inorganic alcohol, concentrate and then extract, separate and pass through ammonia water to obtain the crude product and the purification treatment of the crude product; glycine ethyl ester hydrochloride first adopts ether and ammonia to be dissociated into glycine ethyl ester; the purification process includes (S )- The crude product of oxiracetam is dissolved in its benign solvent to make a saturated solution, and then diffused with its poor solvent in a closed environment. The main raw material of the present invention is cheap and easy to obtain and environmental protection; The present invention adopts glycine ethyl ester hydrochloride to carry out described dissociation treatment, has effectively reduced the consumption of the material in the reaction, has reduced cost, and also played a positive role to the yield of reaction at the same time. role. The (S)-oxiracetam prepared by the invention has an HPLC purity of more than 99.0%, a high yield of up to 36%, mild reaction conditions and simple operation, which is favorable for industrial scale production.

Description

A kind of method for preparing (S)-oxiracetam

technical field

The invention relates to a method for preparing oxiracetam, in particular to a method for preparing (S)-oxiracetam, which belongs to the field of chemical synthesis. the

Background technique

Oxiracetam is a nootropic drug synthesized for the first time in 1974 by the Italian Skelebechem Company. The drug was launched in Italy in 1987. Oxiracetam is composed of two isomers (S) - A racemate of oxiracetam ((S)-oxiracetam) and (R)-oxiracetam ((R)-oxiracetam). The report on oxiracetam discloses that it is a synthetic hydroxyaminobutyric acid (GABOB) cyclic derivative, which can promote ATP in the brain, promote the synthesis of acetylcholine and enhance the conduction of nerve excitation, and it can prevent retrograde neuropathy caused by hypoxia. Sexual amnesia has improvement effect, can strengthen memory, improves learning ability, is one of effective drugs for treating diseases such as Alzheimer's dementia (AD), cerebrovascular dementia (VD). the

Regarding the report on the synthesis of (S)-oxiracetam, U.S. Patent 4,797,496 and WO 93/06826 disclose the method for preparing oxyracetam, the method disclosed in this document includes obtaining chiral alkyl from chiral β-hydroxybutyrolactone 3,4-epoxybutyrate, react the resulting product with N-protected glycinamide and make the resulting product carry out N deprotection, then obtain optically pure oxyracetam through cyclization, the steps of this method are relatively few, but due to the manual The synthetic yield of permanent alkyl 3,4-epoxybutyrate is extremely low and causes the high cost of this method. U.S. Patent No. 4,173,569 describes another (s)-oxiracetam synthesis method: (s)-γ-amino-β-hydroxybutyric acid is the starting material, the hydroxyl group is protected by a silylating agent, and the cyclization The final product is reacted with ethyl haloacetate, and the reaction product is through deprotection, ammonolysis, and finally obtains the target compound; this kind of preparation method is not suitable for industrial scale production, and the use of protecting groups to protect the hydroxyl group will increase the reaction steps and waste Raw materials take a long time, increase the cost and reduce the total yield. the

Contents of the invention

The purpose of the present invention is to provide a method for preparing (S)-oxiracetam with high yield and high purity, which is especially suitable for pharmaceutical applications. the

The object of the invention is achieved through the following technical solutions:

A method for preparing (S)-oxiracetam, characterized in that: using ethyl glycine hydrochloride and (S)-4-halo-3-hydroxyl-butyric acid ethyl ester as raw materials in alcohol solvent and alkaline Reaction under conditions, washing with inorganic alcohol, concentration, extraction, separation and introduction of ammonia water to obtain (S)-oxiracetam crude product and purification treatment of the crude product, the glycine ethyl ester hydrochloride first uses ether and ammonia gas Free into glycine ethyl ester; the purification process includes dissolving the (S)-oxiracetam crude product in its benign solvent, and making a saturated solution at room temperature, and then diffusing it with its poor solvent in a closed environment. the

The purification process of the crude product of the present invention is to dissolve the crude product in water and collect it through a strong acidic cation exchange resin, and then neutralize the collected solution through a strong basic anion exchange resin, so that the pH value of the collected solution is neutral. Complete; then the crude product after the concentration of the collected solution is dissolved in its benign solvent, and made into a saturated solution at room temperature, and then diffused with its poor solvent in a closed environment. the

In order to improve exchange capacity and exchange speed, the strongly acidic cation exchange resin of the present invention is preferably 732# strongly acidic cation exchange resin; the strongly basic anion exchange resin of the present invention is preferably 711# strongly basic anion exchange resin. the

In order to further improve the yield and purity of the (S)-oxiracetam product of the present invention, in the purification process of the present invention, the consumption of the strongly acidic cation exchange resin is: the crude product: the strongly acidic cation exchange resin = 1 gram: 6 milliliters. the

The good solvent of the present invention refers to (S)-oxiracetam in which the solubility is greater than 10 grams/100 grams of solvent, and the poor solvent refers to (S)-oxiracetam in which the solubility is below 1 gram/100 grams Solvents, the definitions of good solvents (easy soluble solvents) and poor solvents (slightly soluble or poorly soluble solvents) are known to those skilled in the art. the

In order to make the obtained (S)-oxiracetam more pure, the good solvent of the present invention is preferably dehydrated alcohol or n-butanol; the poor solvent of the present invention is preferably anhydrous ether, sherwood oil or normal hexane; wherein the reagent used All can be of analytical or chemical purity grade. the

In order to further make the (S)-oxiracetam purity higher and the crystals more stable, the amount of the poor solvent of the present invention is 3-8 times the volume of the (S)-oxiracetam saturated solution, and the preferred amount is 5-6 times. the

In the present invention, the diffusion temperature of the poor solvent is preferably 21-23° C., and the diffusion time is preferably 5-7 days. the

Specifically, the purification process of the present invention is to dissolve the crude product in water and collect it through 732# strong acidic cation exchange resin, and then neutralize the collected solution through 711# strong basic anion exchange resin to make the pH of the collected solution Complete when the value is neutral, the crude product is dissolved in water and carried out ion exchange resin treatment, wherein the crude product: water=1 gram: 0.6 milliliters, the crude product: the 732# strongly acidic cation exchange resin=1 gram: 6 milliliters; then the thick product after the concentrated solution collected by neutralization is dissolved in absolute ethanol or n-butanol, stirred at 18°C to make a saturated solution, and in a closed environment, use 5.8 times the volume of the saturated solution without Water diethyl ether was diffused at 22°C for 6 days, and the precipitated crystals were filtered and dried to obtain (S)-oxiracetam product. the

In order to make the reactant and product easy to dissolve and the treatment after the reaction is completed, the alcohol solvent of the present invention is preferably anhydrous methanol or absolute ethanol; because the product is easily destroyed under strong alkali conditions, in order to form an environment conducive to product stability in the reaction process , the alkaline condition in the reaction process of the present invention is by adding inorganic base control, preferably adding sodium bicarbonate; (S)-4-halo-3-hydroxyl-butyric acid ethyl ester of the present invention preferably adopts (S)-4-chloro -3-Hydroxy-butyric acid ethyl ester. the

Due to the unstable characteristics of glycine ethyl ester, the raw material adopts glycine ethyl ester hydrochloride but in essence glycine ethyl ester is participating in the reaction. In order to reduce the consumption of reaction raw materials in the reaction process of the present invention and reduce costs, more fully use glycine Ethyl ester hydrochloride is dissociated into ethyl glycine to increase the yield. In the present invention, it is preferable to add ethyl glycine hydrochloride to ethyl ether, and then feed ammonia gas at low temperature. the

In the free treatment process of glycine ethyl ester hydrochloride in the present invention, in order to further fully free glycine ethyl ester, the temperature for feeding ammonia gas is 0～-5°C, more preferably -4°C～-5°C , wherein the proportion of glycine ethyl ester hydrochloride, ether and ammonia is 1mol: 1000-1500ml: 1-1.5mol. the

In order to further improve the yield, the dosage ratio of each material of the present invention is preferably glycine ethyl ester in mol ratio: sodium bicarbonate: (S)-4-chloro-3-hydroxyl-butyric acid ethyl ester=1: 0.8～1.3: 1～1.5, the consumption of described anhydrous methanol is 5～10 times of sodium bicarbonate, by weight; More preferably, ethyl glycine: sodium bicarbonate: (S)-4-chloro-3-hydroxyl- Ethyl butyrate=1:1.3:1.5, the amount of anhydrous methanol is 9 times that of sodium bicarbonate. the

Specifically, the preparation of the (S)-oxiracetam crude product of the present invention is to first add glycine ethyl ester hydrochloride into anhydrous ether, ice-cool to -4°C ~ -5°C, feed ammonia gas, filter, and The filtrate is concentrated to obtain ethyl glycine, wherein the ratio of ethyl glycine hydrochloride, ether and ammonia is 1mol: 1000-1500ml: 1-1.5mol; then add sodium bicarbonate and anhydrous methanol, drop (S) -4-chloro-3-hydroxyl-butyric acid ethyl ester, the time for the dropwise addition of (S)-4-chloro-3-hydroxyl-butyric acid ethyl ester is 2 to 3 hours, the pH is controlled to be 8 to 9, and the reaction 25 to 27 hours, the reaction temperature is 65 to 70°C; filter, wash the filtrate fully with ethanol, concentrate, dissolve the concentrate in water, add chloroform 4 times the weight of the filtrate to extract, concentrate the water phase, and separate by column chromatography. Add ammonia water with a concentration of 25% to 28% by weight, and react at 20 to 30°C for 5 to 8 hours to obtain the crude product of (S)-oxiracetam; the ethyl glycine: sodium bicarbonate: (S) -4-chloro-3-hydroxyl-butyric acid ethyl ester=1:0.8～1.3:1～1.5, in molar ratio; the amount of the anhydrous methanol is 5～10 times of the weight of sodium bicarbonate. the

In order to further improve the yield of the present invention to prepare (S)-oxiracetam product, the preparation of (S)-oxiracetam crude product of the present invention is to add glycine ethyl ester hydrochloride in anhydrous ether earlier, ice-cooled to -4°C～-5°C, feed ammonia gas, filter, and concentrate the filtrate to obtain glycine ethyl ester, wherein the ratio of glycine ethyl ester hydrochloride, ether and ammonia gas is 1mol: 1150ml: 1.1mol; Water methanol, sodium bicarbonate and dropwise addition of (S)-4-chloro-3-hydroxy-butyric acid ethyl ester, the dropping time is 2.8 hours, the pH is controlled at 8.5, the reaction temperature is 65 ° C, and the reaction is 27 hours; Filtrate, fully wash the filtrate with ethanol, concentrate, the concentrate is dissolved in water, then add chloroform of 4 times the weight of the filtrate to extract, concentrate the water phase, separate by column chromatography, and finally add ammonia water with a concentration of 27% by weight, at 22 ℃ for 5 hours to obtain (S)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide crude product; the glycine ethyl ester: sodium bicarbonate: (S)-4-chloro-3-hydroxyl- Ethyl butyrate=1:1.3:1.5, in molar ratio; the amount of anhydrous methanol is 9 times of the weight of sodium bicarbonate. the

The present invention has the following beneficial effects:

1, the main raw material that the present invention uses is (S)-4-halo-3-hydroxybutyric acid ethyl ester and glycine ethyl ester hydrochloride, all are commercially available commodity, and raw material is cheap and easy to get and environmental protection, pollution-free; Simultaneously , the present invention first carries out the described free treatment of glycine ethyl ester hydrochloride, which effectively reduces the consumption of materials in the reaction, reduces the cost, and also plays a positive role in the yield of the reaction. The yield of (S)-oxiracetam prepared in the present invention is high, can be as high as 36%, and reaction condition is mild, cycle is short, and operation is simple and is conducive to industrial scale production, and the (S)-oxiracetam product HPLC that prepares simultaneously The purity is above 99.0%. the

2. The present invention adopts ion exchange resin treatment in purifying the final product (S)-oxiracetam. Compared with the silica gel column chromatography method in the prior art, although the treatment effect is equivalent, on the one hand, the ion exchange resin It can be regenerated and reused many times, which reduces the cost. On the other hand, the ion exchange resin is eluted with pure water, which avoids the use of organic solvents, has no pollution, and is more suitable for large-scale industrial production. The present invention selects appropriate (S)-oxiracetam benign solvent dissolution and poor solvent diffusion methods, which effectively reduces the impurity content and significantly improves the quality of the final product, and most of the organic solvents used have low toxicity and low pollution. The water used in the post-treatment process is more pollution-free and non-toxic, so the invention is not only suitable for industrial production, but also meets the national environmental protection requirements. the

Detailed ways

The present invention is specifically described below through the examples, it is necessary to point out that the following examples are only used to further illustrate the present invention, and can not be interpreted as limiting the protection scope of the present invention, those skilled in the art can according to above-mentioned this SUMMARY OF THE INVENTION Some non-essential improvements and adjustments are made to the present invention. the

Example 1

A method for preparing (S)-oxiracetam, carried out as follows:

1. Preparation of crude product:

(a) First add glycine ethyl ester hydrochloride into anhydrous ether, ice-cool to -4°C ~ -5°C, pass through ammonia gas, filter, and concentrate the filtrate to obtain glycine ethyl ester, wherein glycine ethyl ester hydrochloride, The ratio of ether to ammonia is 139.6g: 1150ml: 18.7g; add sodium bicarbonate 109.2g, anhydrous methanol 983ml and dropwise (S)-4-chloro-3-hydroxyl-butyric acid ethyl ester 250.0g, The dropping time is 2.8 hours, keeping pH8.5 and temperature at 65°C, and reacting for 27 hours;

(b) filter, fully wash the filtrate with ethanol, concentrate, the concentrate is dissolved in water, then add 4 times the weight of the filtrate in chloroform for extraction, concentrate the water phase, and separate by column chromatography; finally add the ammoniacal liquor with a mass concentration of 27%, React at 22°C for 5 hours to obtain (S)-oxiracetam crude product;

Wherein ethyl glycine: sodium bicarbonate: (S)-4-chloro-3-hydroxyl-butyric acid ethyl ester=1: 1.3: 1.5, in terms of molar ratio, the consumption of anhydrous methanol is 9 times of sodium bicarbonate weight ;

2. Purification of crude product:

(a) dissolving the above-mentioned crude product in water, passing through 732# strongly acidic cation exchange resin, and then neutralizing and collecting the solution and concentrating through 711# strongly basic anion exchange resin; described crude product: water=1 gram: 0.6 milliliters, Described crude product: described strongly acidic cation exchange resin=1 gram: 6 milliliters;

(b) Then the crude product after the concentrated solution collected by neutralization is dissolved in absolute ethanol, stirred at 18° C. to make a saturated solution, and anhydrous ether of 5.8 times the volume of the saturated solution is used in a closed environment at 22 Diffusion at ℃ for 6 days, the precipitated crystals were filtered and dried to obtain (S)-oxiracetam product. the

The HPLC purity of the finally prepared (S)-4-hydroxy-2-oxo-N-pyrrolidineacetamide product is up to 99.22%, and the yield is as high as 36%. the

Example 2

A method for preparing (S)-oxiracetam, carried out as follows:

1. Preparation of crude product:

(a) Using anhydrous ether and ammonia to dissociate ethyl glycine hydrochloride into ethyl glycine, add sodium carbonate, anhydrous methanol and drop (S)-4-bromo-3-hydroxy-butyric acid ethyl ester, The dropping time is 2.5 hours, and the reaction is 25 hours at pH 8.0 and a temperature of 70°C;

(b) Filtrate, fully wash the filtrate with ethanol, concentrate, dissolve the concentrate in water, add 5 times the weight of the filtrate in dichloromethane for extraction, concentrate the water phase, and separate by column chromatography; finally add ammonia water and react at 20°C Obtain (S)-oxiracetam crude product in 7 hours;

Wherein ethyl glycine: sodium carbonate: (S)-4-bromo-3-hydroxyl-butyric acid ethyl ester=1: 0.5: 1, in mol ratio, the consumption of anhydrous methanol is 6 times of sodium carbonate weight;

2. Purification of crude product:

(a) dissolve the above-mentioned crude product in water, pass through 732# strongly acidic cation exchange resin, then pass through 711# strong basic anion exchange resin to neutralize and collect solution, concentrate; described crude product: water=1 gram: 0.6 milliliter , the crude product: the strongly acidic cation exchange resin=1 gram: 10 milliliters;

(b) Then the crude product after the concentration of the solution collected by neutralization is dissolved in n-butanol, stirred at 25°C to make a saturated solution, and in a closed environment, use petroleum ether of 4 times the volume of the saturated solution at 21°C After 5 days of diffusion, the precipitated crystals were filtered and dried to obtain (S)-oxiracetam product. the

The HPLC purity of the finally prepared (S)-oxiracetam product reaches 99.01%, and the yield reaches 35%. the

Example 3

A kind of preparation method of (S)-oxiracetam, carry out as follows:

1. Preparation of crude product:

(a) ethyl ether and ammonia are used to dissociate ethyl glycine hydrochloride into ethyl glycine, drop (S)-4-iodo-3-hydroxyl-butyric acid ethyl ester, add absolute ethanol and sodium bicarbonate, and The above-mentioned adding time is 2.3 hours, and the pH8.5 and the temperature are kept at 67°C for 28 hours;

(b) Then fully wash and concentrate with ethanol, then add 6 times the amount of ethyl acetate of the filtrate to extract, concentrate, and separate by column chromatography; finally add concentrated ammonia water and react at 30°C for 8 hours to obtain (S)-Azurene Crude Piracetam;

Wherein ethyl glycine: potassium bicarbonate: (S)-4-iodo-3-hydroxyl-butyric acid ethyl ester=1: 1.0: 1.0, in terms of molar ratio, the consumption of dehydrated alcohol is 8 times of sodium bicarbonate weight ;

2. Purification of crude product:

(a) Dissolving the above-mentioned crude product in water, passing through 001×7 strongly acidic styrene-based cation exchange resin, and then passing through 201×7 basic styrene-based anion-exchange resin to neutralize and collect the solution and concentrate;

(b) Then the thick product after the concentrated solution collected by neutralization is dissolved in n-butanol, stirred at room temperature to make a saturated solution, diffused with n-hexane in a closed environment, and the precipitated crystals are filtered and dried to obtain (S ) - Oxiracetam product. the

The HPLC purity of the finally prepared (S)-oxiracetam product reaches 99.1%, and the yield reaches 28%. the

Embodiment 4～8:

A preparation method of (S)-oxiracetam is carried out according to the following materials and process parameters, and the rest are the same as in Example 1. the

The HPLC purity of the (S)-oxiracetam product finally obtained in the above examples reaches 99.0%-99.2%, and the yield reaches 28%-34%. the

Claims (10)

1. a method for preparing (S)-oxiracetam, is characterized in that: adopt glycine ethyl ester hydrochloride and (S)-4-halogen-3-hydroxyl-butyric acid ethyl ester as raw material in alcohol solvent and React under alkaline conditions, filter, wash the filtrate with inorganic alcohol, concentrate, then extract, separate and pass through ammonia water to obtain the crude product of (S)-oxiracetam and the purification treatment of the crude product, the glycine ethyl ester hydrochloride must first be used Diethyl ether and ammonia are dissociated into ethyl glycine; the purification process includes dissolving the (S)-oxiracetam crude product in its benign solvent, and making a saturated solution at room temperature, and then using its poor solvent in a closed environment diffusion. 2. The method according to claim 1, characterized in that: the purification process of the crude product is to dissolve the crude product in water and collect it through a strongly acidic cation exchange resin, then neutralize and collect the crude product through a strongly basic anion exchange resin The solution is completed when the pH value of the collected solution is neutral; then the crude product after the concentration of the collected solution is dissolved in its benign solvent, and a saturated solution is made at room temperature, and then in a closed environment Diffusion with its poor solvent. 3. the method for claim 2 is characterized in that: described strong acidic cation exchange resin is preferably 732# strong acidic cation exchange resin; Described strong basic anion exchange resin is preferably 711# strong basic anion exchange resin . 4. The method according to claim 3, characterized in that: in the purification treatment process, the consumption of the strongly acidic cation exchange resin is: the crude product: the strongly acidic cation exchange resin=1 gram: 6 ml. 5. The method according to claim 2 or 4, characterized in that: the good solvent is absolute ethanol or n-butanol; the poor solvent is anhydrous ether, sherwood oil or n-hexane. 6. the method for claim 5 is characterized in that: the consumption of described poor solvent is 3-8 times of (S)-oxiracetam saturated solution volume; The described temperature that adopts poor solvent to diffuse is 21- At 23°C, the diffusion time is 5-7 days. 7. The method according to claim 1, characterized in that: the purification process is to dissolve the crude product in water and collect it through 732# strong acidic cation exchange resin, then neutralize and collect it through 711# strong basic anion exchange resin The solution is completed when the pH value of the collected solution is neutral, and the crude product is dissolved in water and then treated with an ion exchange resin, wherein the crude product: water=1 gram: 0.6 milliliters, the crude product: the 732# strongly acidic cation exchange resin=1 gram: 6 milliliters; Then the thick product after the concentrated solution of neutralization collection is dissolved in dehydrated alcohol or n-butanol, stirs at 18 ℃ to make saturated solution, under airtight environment Diffusion with anhydrous ether of 5.8 times the volume of the saturated solution at 22° C. for 6 days, and filtering and drying the precipitated crystals to obtain (S)-oxiracetam product. 8. the method as claimed in claim 1 or 7, is characterized in that: described alcohol solvent is absolute methanol or dehydrated alcohol, and the alkaline condition in the described reaction process is by adding sodium bicarbonate to regulate and control, and described (S)-4-halogen-3-hydroxyl-butyric acid ethyl ester is (S)-4-chloro-3-hydroxyl-butyric acid ethyl ester; The consumption ratio of each material described is glycine ethyl ester in molar ratio: Sodium bicarbonate: (S)-4-chloro-3-hydroxyl-butyric acid ethyl ester=1: 0.8～1.3: 1～1.5, the consumption of described anhydrous methanol is 5～10 times of sodium bicarbonate, by weight Servings. 9. method as claimed in claim 8, is characterized in that: described free to glycine ethyl ester hydrochloride is that glycine ethyl ester hydrochloride is added in the ether, feeds ammonia at low temperature again; The temperature of the ammonia gas is -4°C to -5°C, and the ratio of the glycine ethyl ester hydrochloride, ether and ammonia is 1mol: 1000-1500ml: 1-1.5mol. 10. The method according to claim 1 or 7, characterized in that: the preparation of the crude product of (S)-oxiracetam is to first add glycine ethyl ester hydrochloride to anhydrous ether, and ice-cool to -4°C ~-5°C, feed ammonia gas, filter, and concentrate the filtrate to obtain glycine ethyl ester, wherein the ratio of glycine ethyl ester hydrochloride, ether and ammonia gas is 1mol: 1000 ~ 1500ml: 1 ~ 1.5mol; then add Sodium bicarbonate and absolute methanol, drop (S)-4-chloro-3-hydroxyl-butyric acid ethyl ester, the time of said dropwise (S)-4-chloro-3-hydroxyl-butyric acid ethyl ester is 2 to 3 hours, control the pH to 8 to 9, react for 25 to 27 hours, and the reaction temperature is 65 to 70°C; filter, wash the filtrate fully with ethanol, concentrate, dissolve the concentrate in water, and then add chloroform 4 times the weight of the filtrate Extraction, concentration of the aqueous phase, separation by column chromatography, and finally adding ammonia water with a concentration of 25% to 28% by weight, and reacting at 20 to 30°C for 5 to 8 hours to obtain the crude product of (S)-oxiracetam; Described ethyl glycine: sodium bicarbonate: (S)-4-chloro-3-hydroxyl-butyric acid ethyl ester=1: 0.8～1.3: 1～1.5, in molar ratio; The consumption of described anhydrous methanol is 5 to 10 times the weight of sodium bicarbonate.