What Is Oxiracetam?

Oxiracetam, English name Oxiracetam, chemical name 4-hydroxy-2-oxopyrrolidine-N-acetamide; 2- (4-hydroxy-2-oxo-1-pyrrolidinyl) acetamide, the The compound can be obtained from methanol as a white microcrystalline powder with a melting point of 165-168 ° C. It is clinically used for the treatment of brain injury and neurological loss, memory and mental retardation.

Chinese name: Oxiracetam
Foreign name: Oxiracetam
CAS number: 62613-82-5

Molecular formula: C6H10N2O3
Molecular weight: 158.15500
Density: 1.416

Introduction to Oxiracetam Compounds

Oxiracetam Basic Information

Chinese name: Oxiracetam

Chinese alias: 4-hydroxy-2-oxopyrrolidine-N-acetamide; 2- (4-hydroxy-2-oxo-1-pyrrolidinyl) acetamide;

English name: Oxiracetam

English alias: 4-Hydroxy-2-oxopyrrolidine-N-acetamide

CAS number: 62613-82-5

Molecular formula: C ₆ H ₁₀ N ₂ O ₃

Structural formula:

Molecular weight: 158.15500

Exact mass: 158.069000

PSA: 83.63000

Oxiracetam physical and chemical properties

Density: 1.416

Melting point: 165-168ºC

Boiling point: 494.6ºC at 760 mmHg

Flash point: 252.9ºC

Refractive index: 1.57

Oxiracetam safety information

Customs code: 2933790090

Danger category code: R36 / 38

Safety instructions: S26-S36

Dangerous goods mark: Xi ^[1]

Oxiracetam synthesis method

1 Oxiracetam method 1:

4-Amino-3-hydroxybutyric acid reacts with bis (trimethylsilyl) amine to protect the hydroxyl group, and then lactamizes to form a lactam. The amino group is alkylated with 2-bromoethyl acetate to produce 2 -Oxo-4-trimethylsiloxy-1-pyrrolidine ethyl acetate, hydrolyzed to remove the protective group on the hydroxyl group, and then ammonolyzed to obtain oxiracetam.

2 Oxiracetam method 2:

1) Preparation of 2- (3-ethoxyformyl-4-hydroxypyrrolidin-2-one-1-yl) ethyl acetate (3)

In a reaction flask, 648 g (3.43 mol) of ethyl iminoacetate, 3600 ml of anhydrous dichloromethane and 572 ml of triethylamine were added, and 619 g (4.11 mol) of 2-ethoxycarbonylacetyl chloride and dichloride were added dropwise at 0 ° C. A solution of 1.1 m of methane (within internal temperature not exceeding 10-15 ° C) was dripped and stirred at room temperature for 2 h. After the reaction was completed, it was left overnight, and the organic layer was separated and dried over anhydrous magnesium sulfate. Filtration and recovery of the solvent under reduced pressure gave the oil (2).

In a reaction flask, add a solution of 75.6 g (0.243 mol) of sodium metal and 2.7 L of absolute ethanol, and add the above reaction (2) and 1.5 L of anhydrous benzene at room temperature, and heat and stir for 6 h. After the reaction was completed, it was cooled to room temperature, extracted several times with water, and the aqueous layers were combined. It was adjusted to pH 1 with concentrated acid, filtered, and dried to obtain a crude product (3). Ethanol was recrystallized to obtain (3). mp175 ~ 179 .

2) Preparation of 2- (2-pyrrolidine-2,4-dione-1-yl) ethyl acetate (4)

In a reaction flask, (3) 20 g (0.077 mol), 200 ml of acetonitrile and 1.8 ml of water were added, and the mixture was heated under reflux for 20 min. After the reaction, the organic layer was separated, and the aqueous layer was extracted several times with acetonitrile. The organic layers were combined and dried over anhydrous sodium sulfate. Filtration, the solvent was recovered from the filtrate under reduced pressure, and the solid was precipitated and dried to obtain (4), mp 87-91 ° C.

3) Preparation of 2- (4-hydroxypyrrolidin-2-one-1-yl) ethyl acetate (5)

In a reaction flask, add 22.25 g (0.12 mol) of (4), 445 ml of anhydrous dimethoxyethane, and after cooling to 0 ° C, add 1.52 g (0.04 mol) of sodium borohydride, at 0-5 ° Stir for 10 min and 0.5 h at room temperature. Acidified with 20% hydrochloric acid and filtered. The solvent was recovered from the filtrate under reduced pressure, and the residue was dissolved in an appropriate amount of dichloromethane and dried over anhydrous magnesium sulfate. Filtration, the solvent was recovered from the filtrate, and the residue was purified by a chromatography column to obtain (5), mp 180 ° C (dec).

4) Synthesis of Oxiracetam (1)

In a reaction flask, 8.9 g (0.048 mol) of (5) and 300 ml of methanol were added, and ammonia was passed to saturation at 0 ° C, and left to stand overnight. After the reaction, the solvent was recovered under reduced pressure. Dissolve the residue in an appropriate amount of dichloromethane, add activated carbon to decolorize, filter, cool, slowly add it to 200 ml of isopropyl ether, precipitate a solid, filter, and dry to obtain oxiracetam (l), mp161 ~ 163 ° C . ^[2]

Oxiracetam uses

Oxiracetam is used in the treatment of brain injury and neurological deficits, memory and mental retardation. ^[1]

Oxiracetam Pharmacopoeia Standard

This product is 4-hydroxy-2-oxo-1-pyrrolidine acetamide. Calculated as dry product, containing C6H10N2O3 should be 98.0% ~ 102.0%

[Properties] This product is white crystalline powder; odorless, slightly sweet.

This product is easily soluble in water, very slightly soluble in methanol or ethanol, and almost insoluble in acetone, chloroform or benzene.

Melting point The melting point of this product (General Regulation 0612 of the Fourth Edition of the Chinese Pharmacopoeia 2015) is 166 ~ 170 ° C.

[Identification] (1) Take about 10mg of this product, add 2ml of water to dissolve, add 1 drop of potassium permanganate test solution and sodium hydroxide test solution, the solution changes from purple to blue and finally to green.

(2) Take about 10mg of this product, add 1 drop of hydrochloric acid to dissolve it, place it in a water bath and evaporate to dryness, add 1 drop each of potassium iodide test solution and 5% potassium iodate solution, the solution will turn brown, and add 1 drop of starch indicator solution Should be blue.

(3) In the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution. (4) The infrared absorption spectrum of this product should be consistent with the control spectrum (spectrum set 1063).

an examination

Optical rotation

Appropriate amount of this product, precisely weighed, dissolved in water and quantitatively diluted to make a solution containing 50mg per 1ml, shake well. According to the law (Chinese Pharmacopoeia 2015 Edition Four General Rules 0621), the optical rotation should be -0.10 ° to + 0.10 °.

Acidity: Take 0.10g of this product, add 10ml of water to dissolve, and measure according to law (Chinese Pharmacopoeia 2015 Edition Four General Principles 0631). The pH value should be 3.5 ~ 5.5.

Clarity of the solution Take 1.0g of this product, add 10ml of water to dissolve, the solution should be clear.

Chloride Take 0.50 g of this product and check it according to law (Chinese Pharmacopoeia 2015 Edition Four General Rules 0801). Compared with the control solution made of 7.0 ml of standard sodium chloride solution, it must not be more concentrated (0.014%).

Take the appropriate amount of this substance, accurately weigh it, add the mobile phase to dissolve and quantitatively dilute it to make a solution containing about 1mg per 1ml, shake it up, and use it as the test solution; precisely measure the appropriate amount of the test solution, and use the mobile phase. Quantitatively dilute to make a solution containing 1g per 1ml as a control solution; accurately weigh an appropriate amount of oxiracetamate (impurity I) reference substance, add mobile phase to dissolve and quantitatively dilute to a solution containing about 3g per 1ml, As a reference solution. According to the chromatographic conditions under the content determination item, accurately measure 20 l each of the test solution, control solution and reference solution, and inject them into the liquid chromatograph respectively, and record the chromatogram to 3 times the peak component retention time. If the chromatogram of the test solution has chromatographic peaks consistent with the retention time of impurities I, the peak area calculated according to the external standard method shall not exceed 0.3%; the area of other single impurity peaks shall not be larger than the main peak area of the control solution (0.1% ), The sum of the peak areas of other impurities should not be greater than 5 times (0.5%) the area of the main peak of the control solution. The chromatograms of the test solution chromatograms that are smaller than 0.3 times the area of the main peak of the control solution are ignored.

Residual solvents: methanol, ethanol, and dichloromethane: take 0.5g of this product, weigh it accurately, place it in a 20ml headspace bottle, add 5ml of 10% N, N-dimethylformamide precisely, dissolve, seal, and use it as the test solution ; Take another amount of methanol, ethanol and dichloromethane, accurately weigh, add 10% N, N dimethylformamide to dissolve and quantitatively dilute to make 0.3ml of methanol, 0.5mg of ethanol and dichloromethane per 1ml. 0.06mg of the mixed solution, precisely measure 5ml, place it in a 20ml headspace bottle, seal, and use it as a reference solution. According to the determination of residual solvents (Chinese Pharmacopoeia 2015 version of the Draft for General Comment 0861, the second method), 6% cyanopropylphenyl-94% dimethylpolysiloxane (or similar polarity) was used as the fixed solution. The capillary column is a chromatographic column with an initial temperature of 80 ° C for 6 minutes and a rise of 150 ° C at a rate of 10 ° C per minute for 2 minutes; the inlet temperature is 220 ° C; the detector temperature is 250 ° C; headspace The equilibration temperature of the bottle was 85 ° C and the equilibration time was 20 minutes. Take the reference solution headspace sample, and the resolution between each peak should meet the requirements. Take the test solution and the reference solution for headspace injection, record the chromatogram, and calculate the peak area according to the external standard method, which should meet the requirements. Loss on drying Take this product and dry it to constant weight at 105 ° C, and the weight loss should not exceed 0.5% (Chinese Pharmacopoeia 2015 Edition Four General Principles 0831).

Ignition residue Take 1.0g of this product and check it according to law (General Regulations of the Fourth Section of the Chinese Pharmacopoeia 2015 Edition 0841). The residual residue should not exceed 0.1%.

The heavy metal is taken from the residue left by the burning residue, and inspected in accordance with the law (the second law of the General Section of the Chinese Pharmacopoeia 2015 Edition 0821 second method). The heavy metal must not exceed 10 parts per million (for injection) or not exceed 20 parts per million ( For oral use).

[Content determination] Determination according to high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Four General Rules 0512).

Chromatographic conditions and system suitability test Use water-resistant octadecylsilane-bonded silica gel with embedded polar groups as the filler (TechMate C18-ST column, 4.6mm × 250mm, 5m, or equivalent column); The mobile phase was 0.02mol / L sodium dihydrogen phosphate solution; the detection wavelength was 210nm. Take appropriate amounts of oxiracetam and impurity I reference substance, dissolve and dilute with mobile phase to make a solution containing 1g and 3g per 1ml, take 20l, inject it into the liquid chromatograph, and record the chromatogram. The order of the peaks is: impurity I peak, oxiracetam peak. The resolution between the oxiracetam peak and the impurity I peak should be greater than 4.0, and the theoretical number of plates based on the oxiracetam peak should not be less than 5000.

Weigh the appropriate amount of the product accurately by the determination method , add mobile phase to dissolve and quantitatively dilute it to make a solution containing about 0.1mg per 1ml, and accurately measure 20l into the liquid chromatograph and record the chromatogram; Control substance, the same method. Calculate the peak area according to the external standard method.

Oxiracetam pharmacological effects

Oxiracetam is a cyclic GABOB derivative. Animal experiments have confirmed that Oxiracetam can significantly improve learning and memory impairment caused by chemical substances and promote learning and memory. Oxiracetam is extremely toxic. No intramuscular death was observed in mice given 10 g / kg by intragastric administration, 2 g / kg by intragastric administration, and no toxic reactions were observed in rats. Rats took 120 mg / kg orally for 52 weeks, and dogs took 83.3 mg / kg for 52 weeks. No mutagenic and carcinogenic effects and reproductive toxicity. ^[3]

Oxiracetam pharmacokinetics

Oxiracetam is rapidly absorbed orally, and can be quickly distributed to whole body fluids after entering the bloodstream. The peak time (Tp) is about 1h, the peak concentration is (48.34 ± 18.35) (54.96 ± 34.73) g / ml, and the apparent distribution volume V / F (c) is (27.45 ± 21.16) (36.18 ± 28.73) L. The elimination half-life tl / 2 is (3.34 ± 1.59) (4.74 ± 1.41) h, and the total clearance Cl (8) is (6.78 ± 5.50) (11.65 ± 5.40) L / h, and the drug elimination is relatively rapid. About 40% of the prototype drug was excreted in the urine within 48 hours after taking the drug. The excretion rate constants for the elderly and youth groups were 0.1098 ± 0.0306 and 0.1295 ± 0.0390h, respectively; the elimination half-life (1/2) was 6.67 ± 1.98 and 5.88 ± 1.99h, respectively. Oxiracetam was found in normal humans of different ages. The elimination law is basically the same. ^[3]

Oxiracetam indication

Oxiracetam is a nootropic drug for memory and mental impairment caused by mild to moderate vascular dementia, Alzheimer's disease (senile dementia), and brain trauma. ^[3]

Oxiracetam contraindications

Patients with proven allergies to oxiracetam and those with renal insufficiency are contraindicated. ^[3]

Oxiracetam dosage form

1. Capsule: 0.4g.

2. Tablet: 0.4g;

3. Injection: 1g / 5ml. ^[3]

Oxiracetam dosage

1. Oral. 800mg each time, 2 to 3 times a day, severe cases 2 to 8g per day or increase or decrease as required by your doctor.

2. Intravenous or intramuscular injection: 1g each time. ^[3]

Oxiracetam adverse reactions

Oxiracetam did not show any significant adverse reactions in 327 cases of phase II clinical trials. ^[3]

Oxiracetam notes

1. People with renal insufficiency should be very careful when using oxiracetam and reduce the dose.

2. Shaded, sealed, and stored in a cool and dry place. ^[3]

Oxiracetam for pregnant and lactating women:

The safety of this product in pregnant and lactating women is not clear, so it should not be used. ^[4]