CN102603607B - Preparation method of (R)-oxiracetam - Google Patents

Abstract

A preparation method of (R)-oxiracetam, adopting glycine ethyl ester hydrochloride and (R)-4-halo-3-hydroxyl-butyric acid ethyl ester as raw materials to react under alcohol solvent and alkaline conditions, Washing with inorganic alcohol, concentration, extraction, separation and introduction of ammonia water to obtain (R)-oxiracetam crude product and purification treatment of the crude product; the glycine ethyl ester hydrochloride must first be dissociated into glycine ethyl ester hydrochloride with ether and ammonia gas ester. The main raw materials of the present invention are (R)-4-halo-3-hydroxybutyric acid ethyl ester and glycine ethyl ester hydrochloride, the raw materials are cheap and easy to get and are environmentally friendly and pollution-free; The above free treatment effectively reduces the amount of materials used in the reaction, lowers the cost, and also plays a positive role in the yield of the reaction. The preparation of (R)-oxiracetam in the present invention has low cost and high yield up to 33%, mild reaction conditions are favorable for industrial scale production, and the HPLC purity of the prepared (R)-oxiracetam product reaches over 98.5%.

Description

The preparation method of (R)-oxiracetam

technical field

The invention relates to the preparation of oxiracetam, in particular to a preparation method of (R)-oxiracetam. 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). (R)-Oxiracetam is a single enantiomer of oxiracetam with the chemical name: (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide. The nootropic drug oxiracetam is a synthetic hydroxyaminobutyric acid (GABOB) derivative, which is a central nervous system drug that can promote learning, enhance memory, and protect damaged nerve cells. the

US Patents 4,124,594, 4,173,569 and 4,629,797 to ISFSpa disclose a process for preparing optically pure oxyracetam. The methods disclosed in these patents include reacting optically pure (s)-gamma amino-beta-hydroxybutyric acid with a silylating agent to protect the hydroxyl group, allowing the resulting product to react with the formula Hal( CH ₂ COOR) aliphatic acid halogen compound reaction, followed by cyclization and hydrolysis to obtain optically pure oxyracetam. Although this method provides optically pure oxyracetam, its disadvantages are: expensive raw materials, many steps, low yield, and high cost. US Patents 4,824,966, 4,843,166 and 5,276,164 to Lonza Ltd disclose the preparation of oxyracetam and its intermediates. The process disclosed in these patents involves reacting 4-(C ₁ -C ₂ )-alkoxy-3-pyrrolin-2-one-1-yl-acetic acid (C ₁ -C ₄ )-alkyl ester with trichloro Methylsilane is reacted to protect the hydroxyl group, and the resulting product is then subjected to hydrogenation and amidation. According to this method, racemic oxyracetam is obtained by hydrogenation double bond reduction. Therefore, this method has the disadvantage that it is not suitable for the preparation of optically pure oxyracetam. In addition, 4-(C1-C2)-alkoxy-3-pyrrolin-2-on-1-yl-acetic acid (C1-C4)-alkyl esters were prepared in low yields. But up to now, no related literature has reported the preparation method of (R)-oxiracetam.

Contents of the invention

The purpose of the present invention is to provide a preparation method of (R)-oxiracetam with low cost and high yield. the

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

The preparation method of (R)-oxiracetam is characterized in that: using glycine ethyl ester hydrochloride and (R)-4-halo-3-hydroxyl-butyric acid ethyl ester as raw materials under alcohol solvent and alkaline conditions The reaction is filtered, washed with inorganic alcohol, concentrated, then extracted, concentrated in the water phase, and passed through ammonia water to obtain the crude product of (R)-oxiracetam and the purification treatment of the crude product; the glycine ethyl ester hydrochloride is first Ethyl ether and ammonia are used to dissociate into ethyl glycine. the

In order to further increase the yield of (R)-oxiracetam in the present invention, column chromatography separation is carried out after the above-mentioned extraction and concentration of the aqueous phase, and then ammonia water is introduced to prepare the crude product of (R)-oxiracetam. the

In order to reduce the consumption of reaction raw materials in the reaction process of the present invention, reduce cost, simultaneously with glycine ethyl ester hydrochloride free more fully to improve yield and be beneficial to purifying treatment, the present invention preferably glycine ethyl ester hydrochloride free Ethyl ester hydrochloride was added to ether, and ammonia gas was introduced at low temperature. the

In the process of dissociating ethyl glycine hydrochloride in the present invention, in order to further fully dissociate and obtain ethyl glycine, the temperature for feeding ammonia gas is 2°C to -5°C, more preferably -3°C to -5°C. ℃, wherein the proportion of glycine ethyl ester hydrochloride, ether and ammonia is 1mol: 1100～1300ml: 1.2～1.7mol. the

Specifically, the free treatment of glycine ethyl ester hydrochloride in the present invention is to add glycine ethyl ester hydrochloride into anhydrous ether, ice-cool to -3°C ~ -5°C, feed ammonia gas, filter, and concentrate the filtrate Obtain glycine ethyl ester, wherein the consumption ratio relation of glycine ethyl ester hydrochloride, ether and ammonia gas is 1mol: 1250ml: 1.5mol. the

In order to make the reactants and products easy to dissolve and the treatment after the reaction is completed, the alcohol solvent of the present invention is preferably absolute methanol or absolute ethanol. the

(R)-4-halo-3-hydroxyl-butyric acid ethyl ester of the present invention preferably adopts (R)-4-chloro-3-hydroxyl-butyric acid ethyl ester; the alkali that the present invention adds preferably adopts sodium carbonate or sodium bicarbonate . the

In order to further improve the yield and be more beneficial to purification treatment, the consumption ratio of each material of the present invention is preferably glycine ethyl ester in terms of molar ratio: sodium bicarbonate: (R)-4-chloro-3-hydroxyl-butyric acid ethyl ester=1 : 1～1.5: 1.2～1.8, the consumption of described dehydrated alcohol is 3～7 times of sodium bicarbonate, in parts by weight; More preferably, ethyl glycine: sodium bicarbonate: (R)-4-chloro -3-hydroxyl-butyric acid ethyl ester=1:1.4:1.6, the consumption of dehydrated alcohol is 4 times of sodium bicarbonate. the

More specifically, the preparation of the crude product of (R)-oxiracetam in the present invention is to first add glycine ethyl ester hydrochloride into anhydrous ether, ice-cool to -4°C ~ -5°C, pass through ammonia gas, filter, Concentrate the filtrate to obtain glycine ethyl ester; then add absolute ethanol, sodium bicarbonate and dropwise add (R)-4-chloro-3-hydroxy-butyric acid ethyl ester, the dropwise addition of (R)-4-chloro-3 -Hydroxy-butyric acid ethyl ester time is 3 to 3.5 hours, the pH is controlled to 8 to 9, the reaction temperature is 65 to 75 ° C, and the reaction is 20 to 30 hours; filter, fully wash the filtrate with methanol or ethanol, concentrate, concentrate The product was dissolved in water, then added 4 times the weight of the filtrate in chloroform for extraction, and the aqueous phase was concentrated; finally, concentrated ammonia was added, and reacted for 4 to 7 hours at 25～32°C; the glycine ethyl ester: sodium bicarbonate: (R )-4-chloro-3-hydroxyl-butyric acid ethyl ester=1: 1～1.5: 1.2～1.8, the consumption of described dehydrated alcohol is 3～7 times of sodium bicarbonate weight. the

In order to further improve the yield of (R)-oxiracetam prepared by the present invention, the preparation of (R)-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: 1250ml: 1.5mol; then add anhydrous Ethanol, sodium bicarbonate and the (R)-4-chloro-3-hydroxy-butyric acid ethyl ester were added dropwise for 3 hours, the pH was controlled to be 8.5, the reaction temperature was 75°C, and the reaction was carried out for 28 hours; filtration, Fully wash the filtrate with ethanol, concentrate, then add 4 times the weight of the filtrate in chloroform for extraction, concentrate the water phase, and separate by column chromatography; finally add concentrated ammonia water with a mass percentage concentration of 28%, and react at 30°C for 5 hours; Described glycine ethyl ester: sodium bicarbonate: (R)-4-chloro-3-hydroxyl-butyric acid ethyl ester=1: 1.4: 1.6, in mol ratio, the consumption of dehydrated alcohol is 4 times of sodium bicarbonate weight ; The addition of the 28% concentrated ammonia water is 4-8 times the weight of the column separation product. 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 neutralizing the collected solution and concentrating it is subjected to recrystallization treatment. 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

The recrystallization treatment of the present invention uses ethanol for the first recrystallization treatment, and uses a mixed solvent of methanol/acetone for the second recrystallization treatment. the

In order to further improve the purity of the (R)-oxiracetam product of the present invention, in the purification treatment process of the present invention, the aqueous solution of described crude product presses crude product: water=1 gram: 1.2 milliliters, the strong acidic cation exchange resin Consumption is: described crude product: described strongly acidic cation exchange resin=1 gram: 13 milliliters; Described the consumption that carries out recrystallization treatment for the first time with ethanol is: described concentrated crude product: ethanol=1 gram: 1.5 milliliters; The consumption in the described second recrystallization process is: crude product after the first recrystallization: methyl alcohol=1 gram: 2 milliliters, wherein the volume ratio of methanol and acetone in the mixed solvent of methanol/acetone is 1 : 2. the

The present invention has the following beneficial effects:

1, the main raw material that the present invention uses is (R)-4-halogen-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 (R)-oxiracetam prepared by the present invention has low cost, the yield can be as high as 33%, the reaction conditions are mild, the cycle is short, and the operation is simple, which is beneficial to industrial scale production, and the (R)-oxiracetam prepared at the same time The HPLC purity of the product is above 98.5%. the

2. The present invention adopts ion exchange resin treatment in purifying the final product (R)-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. Most of the organic solvents used in the present invention have low toxicity and low pollution, and the water used in the post-treatment process is pollution-free and non-toxic, so the present 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

The preparation method of (R)-oxiracetam, carries out as follows:

1. Preparation of crude product:

(a) Add 139.6 g of ethyl glycine hydrochloride into 1250 ml of anhydrous ether, cool it to -4°C and blow in 25.5 g of ammonia gas to dissociate ethyl glycine hydrochloride into ethyl glycine, wherein ethyl glycine hydrochloride Salt: anhydrous ether: ammonia gas is 1mol: 1250ml: 1.5mol;

(b) Add absolute ethanol 470ml, sodium bicarbonate 117.6g, dropwise (R)-4-chloro-3-hydroxyl-butyric acid ethyl ester 266.6g in the above-mentioned product, and described dropping time is 3 hours, in React for 28 hours at pH 8.5 and temperature 75°C;

(c) filter, fully wash the filtrate with ethanol, concentrate, dissolve the concentrate in water, then add 4.5 times the weight of the filtrate in chloroform for extraction, concentrate the water phase, and separate by column chromatography; finally add ammonia water with a mass percentage concentration of 28% , reacted at 30°C for 5 hours to obtain the crude product of (R)-oxiracetam, wherein the consumption of 28% ammonia water was 6 times of the weight of the product separated by column chromatography;

Wherein ethyl glycine: sodium bicarbonate: (R)-4-chloro-3-hydroxyl-butyric acid ethyl ester=1: 1.4: 1.6, in mol ratio, the consumption of dehydrated alcohol is 4 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: 1.2 milliliters, Described crude product: described strongly acidic cation exchange resin=1 gram: 13 milliliters;

(b) then carry out the first recrystallization treatment with ethanol to the above-mentioned crude product after ion exchange resin concentration, and use the mixed solvent of methanol/acetone to carry out the second recrystallization treatment to obtain (R)-oxiracetam product; The crude product concentrated after passing through the ion exchange resin: ethanol=1 gram: 1.5 milliliters; The crude product after the described first recrystallization: methanol=1 gram: 2 milliliters, wherein in the mixed solvent of methanol/acetone, methanol and The volume ratio of acetone is 1:2. the

The HPLC purity of the finally prepared (R)-oxiracetam product reaches 99.5%, and the yield is as high as 33%. the

Example 2

The preparation method of (R)-oxiracetam, carries out as follows:

1. Preparation of crude product:

(a) Add glycine ethyl ester hydrochloride to anhydrous ether, cool to -4°C and pass through ammonia gas to dissociate glycine ethyl ester hydrochloride into glycine ethyl ester, wherein glycine ethyl ester hydrochloride: anhydrous ether : Ammonia is 1mol: 1300ml: 1.2mol;

(b) Add anhydrous methanol, sodium carbonate, (R)-4-iodo-3-hydroxy-butyric acid ethyl ester to the above product, and react at pH 8 and temperature at 65°C for 20 hours;

(c) Filtrate, fully wash the filtrate with ethanol, concentrate, dissolve the concentrate in water, then add ethyl acetate 5 times the weight of the filtrate for extraction, concentrate the water phase, and separate by column chromatography; finally add a mass percent concentration of 27% Aqueous ammonia was reacted at 25°C for 7 hours to obtain the crude product of (R)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide, wherein the amount of 27% ammonia was 8 times the weight of the product separated by column chromatography; Wherein ethyl glycine: sodium carbonate: (R)-4-iodo-3-hydroxyl-butyric acid ethyl ester=1: 1.5: 1.8, in mol ratio, the consumption of anhydrous methanol is 7 times of sodium carbonate weight;

2. Purification of crude product:

(a) dissolve the above-mentioned crude product in water, pass through 001×7 strong acidic styrene-based cation exchange resin, and then pass through 201×7 basic styrene-based anion-exchange resin to neutralize and collect the solution and concentrate; the crude product: water =1 gram: 0.6 milliliters, described crude product: described strongly acidic cation exchange resin=1 gram: 10 milliliters;

(b) then carry out the first recrystallization treatment with ethanol to the crude product concentrated by the ion exchange resin, and use the mixed solvent of methanol/acetone to carry out the second recrystallization treatment to obtain the (R)-oxiracetam product; The crude product concentrated after passing through the ion exchange resin: ethanol=1 gram: 1.5 milliliters; The crude product after the described first recrystallization: methanol=1 gram: 1 milliliter, wherein in the mixed solvent of methanol/acetone, methanol and The volume ratio of acetone is 1:2. the

The HPLC purity of the finally obtained (R)-oxiracetam product reaches 99.2%, and the yield reaches 28%. the

Example 3

The preparation method of (R)-oxiracetam, carries out as follows:

1. Preparation of crude product:

(a) Glycine ethyl ester hydrochloride is suspended in chemically pure ether, feeds ammonia gas then and glycine ethyl ester hydrochloride is freed into glycine ethyl ester;

(b) Add absolute ethanol, sodium bicarbonate, dropwise (R)-4-bromo-3-hydroxyl-butyric acid ethyl ester to the above product, the time for the addition is 3.5 hours, at a pH of 9 and a temperature of 70 Reaction at ℃ for 20-26 hours;

(c) then filter, fully wash the filtrate with ethanol, concentrate, and the concentrate is dissolved in water, then add 4 times the weight of the filtrate in chloroform for extraction, and concentrate the water phase; finally add the ammonia water with a mass percentage concentration of 26%, at 28 ° C Down reaction made (R)-oxiracetam crude product in 6 hours;

Wherein ethyl glycine: sodium bicarbonate: (R)-4-bromo--3-hydroxyl-butyric acid ethyl ester=1: 1: 1.2, in terms of molar ratio, the consumption of dehydrated alcohol is 3% of the weight of sodium bicarbonate times;

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: 10 milliliters;

(b) then carry out the first recrystallization treatment with ethanol to the crude product concentrated by the ion exchange resin, and use the mixed solvent of methanol/acetone to carry out the second recrystallization treatment to obtain the (R)-oxiracetam product; The crude product concentrated after passing through the ion exchange resin: ethanol=1 gram: 1.5 milliliters; The crude product after the described first recrystallization: methanol=1 gram: 2 milliliters, wherein in the mixed solvent of methanol/acetone, methanol and The volume ratio of acetone is 1:3. the

The HPLC purity of the finally prepared (R)-oxiracetam product reaches 99.3%, and the yield is as high as 26%. the

Embodiment 4～8:

A preparation method of (R)-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 (R)-oxiracetam product finally obtained in the above examples reaches above 98.5%-99.26%, and the yield reaches 28%-33%. the

Claims (2)

1. the preparation method of a (R)-oxiracetam, it is characterized in that: the preparation of described (R)-oxiracetam crude product is first glycine ethyl ester hydrochloride to be added in anhydrous diethyl ether, ice-cold to-4 ℃～-5 ℃, pass into ammonia, filter, filtrate concentrating obtained to glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia pass is 1mol:1100～1300ml:1.2～1.7 mol; Then add dehydrated alcohol, sodium bicarbonate and dropping (R)-4-chloro-3-hydroxyl-ethyl butyrate, the time of described dropping (R)-4-chloro-3-hydroxyl-ethyl butyrate is 3～3.5 hours, controlling pH is 8～9, temperature of reaction is 65～75 ℃, reacts 20～30 hours; Filter, filter residue methyl alcohol or ethanol are fully washed, concentrated, enriched material is soluble in water, then adds the chloroform of 4 times of filtrate weight to extract, and after water is concentrated, column chromatography for separation obtains (R)-4-hydroxyl-2-OXo-1-pyrrolidine ethyl acetate; Finally add again 28% strong aqua, at 25～32 ℃, react 4～7 hours; Described glycine ethyl ester: sodium bicarbonate: (R)-4-chloro-3-hydroxyl-ethyl butyrate=1:1～1.5:1.2～1.8, the consumption of described dehydrated alcohol is 3～7 times of sodium bicarbonate weight; The add-on of described 28% strong aqua is 4-8 times of described column chromatography for separation product weight; The purification process of described thick product is that thick product is also collected with passing through storng-acid cation exchange resin after water dissolution, then passes through in strongly basic anion exchange resin and the solution of collection, and the pH value that makes the solution of described collection completes while being neutral; Then the thick product after the solution of neutralization being collected concentrates carries out recrystallization processing;

Described recrystallization processing is to adopt ethanol to carry out recrystallization processing for the first time, adopts the mixed solvent of methanol/acetone to carry out recrystallization processing for the second time;

Describedly with the consumption that ethanol carries out recrystallization processing be for the first time: described thick product after concentrated: ethanol=1 gram: 1.5 milliliters; Consumption in the described processing of recrystallization is for the second time: the thick product after recrystallization for the first time: methyl alcohol=1 gram: 2 milliliters, wherein in the mixed solvent of methanol/acetone, the volume ratio of methyl alcohol and acetone is 1:2.

2. preparation method as claimed in claim 1, is characterized in that: described storng-acid cation exchange resin is 732# storng-acid cation exchange resin, and described strongly basic anion exchange resin is 711# strongly basic anion exchange resin; The aqueous solution of described thick product is pressed thick product: water=1 gram: 1.2 milliliters, the consumption of described storng-acid cation exchange resin is: described thick product: described storng-acid cation exchange resin=1 gram: 13 milliliters.