Method for preparing phenytoin sodium

Abstract

The invention discloses a method for preparing phenytoin sodium, which comprises the following steps: sequentially adding benzoin and ferric trichloride into an aqueous solution of alcohol, stirring and heating to reflux, cooling and filtering to obtain a phenytoin sodium intermediate 1; carrying out reflux reaction on the intermediate 1 and urea under alkaline conditions, adding purified water, filtering to remove impurities, neutralizing filtrate with hydrochloric acid, crystallizing and filtering to obtain phenytoin; sequentially adding phenytoin, sodium hydroxide and a low-boiling-point solvent, carrying out heating reflux reaction, cooling to room temperature after the reaction is ended, filtering, and drying to constant weight in a nitrogen-vacuum system at room temperature to obtain phenytoin sodium; the method has the beneficial effects that ferric trichloride is used as an oxidizing agent, so that the method is energy-saving and environment-friendly, and the prepared intermediate 1 has few impurities; the finished product is prepared only by using a volatile solvent, is easy to remove and does not need to be dried by a drying oven, nitrogen-vacuum is used for drying at room temperature, the energy consumption is low, no high-temperature destroyed impurities are generated, the impurities are few, and the purity is high; the method has the advantages of cheap and easily available raw materials, simple operation and few three wastes.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical preparation, and particularly relates to a method for preparing phenytoin sodium. Background Art

[0002] Chemical name of phenytoin sodium: 5,5-diphenylhydantoin sodium salt, molecular formula: C 15 H 12 NaO2, molecular weight: 275.26.

[0003] Phenytoin sodium is used to control tonic-clonic seizures, partial seizures, or a combination of the two; to prevent and treat epileptic seizures during or after neurosurgery and / or severe head injury; to treat trigeminal neuralgia, but only as a second-line treatment when carbamazepine is ineffective or the patient is intolerant to carbamazepine; it is also used for ventricular and supraventricular arrhythmias caused by digitalis poisoning, but is less effective for arrhythmias caused by various other reasons.

[0004] The preparation method of phenytoin sodium with the publication number of Chinese patent document CN113943254A proposes the following route, using ferric chloride as an oxidant instead, without exhaust gas emission, convenient and safe operation, high product yield and good product quality, but the prepared phenytoin sodium has poor solubility in water and is easy to absorb moisture and deteriorate. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing phenytoin sodium. The phenytoin sodium prepared by the preparation method has high purity and stability, is not easy to absorb moisture and deteriorate, has a simple process, is easy to operate, and is suitable for industrial production.

[0006] To achieve the above object, the present invention provides the following technical solution: a method for preparing phenytoin sodium, comprising the following steps:

[0007] Synthesis of Phenytoin Sodium:

[0008] Add benzoin and ferric chloride to the alcohol aqueous solution in sequence, stir and heat to reflux, cool and filter to obtain phenytoin sodium intermediate 1;

[0009] The intermediate 1 is reacted with urea under alkaline conditions by reflux, purified water is added to filter and impurities are removed, and the filtrate is neutralized with hydrochloric acid and then crystallized and filtered to obtain phenytoin;

[0010] Add phenytoin, sodium hydroxide, and a low boiling point solvent in sequence, heat up and reflux for reaction, cool to room temperature after the reaction is completed, filter, and dry to constant weight in a nitrogen-vacuum system at room temperature to obtain phenytoin sodium;

[0011] The reaction equation is as follows:

[0012]

[0013] As a preferred technical solution of the present invention, the molar ratio of ferric chloride to benzoin is 1.0-2.0:1.

[0014] As a preferred technical solution of the present invention, the molar ratio of the sodium hydroxide to the intermediate 1 is 1:1.0-1.5.

[0015] As a preferred technical solution of the present invention, the molar ratio of urea to intermediate 1 is 1:1.0-1.5.

[0016] As a preferred technical solution of the present invention, the amount of purified water used is 5 to 10 times the mass of the intermediate 1.

[0017] As a preferred technical solution of the present invention, the concentration of the hydrochloric acid used is 15% to 35%.

[0018] As a preferred technical solution of the present invention, the crystallization temperature is 10-40°C.

[0019] As a preferred technical solution of the present invention, the solvent is one or more of dichloromethane, n-hexane and acetone.

[0020] As a preferred technical solution of the present invention, the molar ratio of sodium hydroxide to phenytoin is 1.0 to 1.2.

[0021] As a preferred technical solution of the present invention, the reaction temperature is 40-90°C.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] Using ferric chloride as an oxidant is energy-saving and environmentally friendly, and the prepared intermediate 1 has few impurities;

[0024] The finished product is prepared with only volatile solvents, which are easy to remove and do not require oven drying. Nitrogen-vacuum drying at room temperature consumes less energy and does not cause the formation of impurities that are destroyed by high temperature, resulting in less impurities and higher purity.

[0025] The required raw materials are cheap and easy to obtain, the operation is simple, and less three wastes are produced. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The present invention is a flow chart of the method for preparing phenytoin sodium. DETAILED DESCRIPTION

[0027] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0028] Example 1

[0029] See also Figure 1 , is the first embodiment of the present invention, which provides a method for preparing phenytoin sodium,

[0030] 19 g of purified water, 38 g of anhydrous ethanol, 24.4 g of ferric chloride and 12.5 g of benzoin were put into a 250 ml reaction bottle, stirred, heated to 50°C, kept at 50-60°C for 6 h, cooled to 25°C, filtered, and dried at 80°C for 3 h to obtain 13.18 g of diphenylethylenedione with a yield of 97.2%.

[0031] Add 36 g of purified water and 5.3 g of sodium hydroxide into the reaction bottle, mix well, add 24 g of anhydrous ethanol, 6 g of urea, and 13 g of diphenylethylenedione, heat to 50°C, react at 50-60°C for 3 h, add 0.6 g of activated carbon, decolorize for 1 h, add 100 g of purified water and filter, cool the filtrate to 20°C, add dilute hydrochloric acid dropwise to adjust the pH to 4.8, grow crystals for 2 h, filter to obtain wet phenytoin, and dry at 85°C to obtain 14.3 g of dry phenytoin with a yield of 91.4%.

[0032] 1.9 g purified water and 1.9 g sodium hydroxide were used to prepare alkali solution for later use. 100 ml of dichloromethane and 10 g of phenytoin were added to the reaction bottle, and the temperature was raised to 45 ° C. The alkali solution was added and stirred at 40-45 ° C for 3 h. The temperature was lowered to 20 ° C. The mixture was filtered using a vacuum chromatography column while maintaining the nitrogen pressure at 0.3 MPa. The mixture was dried at room temperature until no water droplets condensed on the column wall. The mixture was dried for 3 h to obtain 10.48 g of dry phenytoin sodium with a yield of 96.3%.

[0033] Example 2

[0034] See also Figure 1 , which is the second embodiment of the present invention, provides a method for preparing phenytoin sodium,

[0035] 20g purified water, 40g anhydrous ethanol, 23.15g ferric chloride and 12.5g benzoin were put into a 250ml reaction bottle, stirred, heated to 40°C, kept at 40-60°C for 6h, cooled to 25°C, filtered, and dried at 80°C for 3h to obtain 13.51g of diphenylethylenedione with a yield of 99.5%.

[0036] Add 20 g of purified water and 5.3 g of sodium hydroxide into the reaction bottle, mix well, add 24 g of anhydrous ethanol, 4.2 g of urea, and 13 g of diphenylethylenedione, heat to 50°C, react at 70-80°C for 3 h, add 0.6 g of activated carbon, decolorize for 1 h, add 65 g of purified water for filtration, cool the filtrate to 20°C, add dilute hydrochloric acid dropwise to adjust the pH to 3.5, grow the crystal for 2 h, filter to obtain wet phenytoin, and dry at 70°C to obtain 13.8 g of dry phenytoin with a yield of 88.2%.

[0037] 1.6g purified water and 1.6g sodium hydroxide were used to prepare alkali solution for later use; 100ml acetone and 10g phenytoin were added into the reaction bottle, the temperature was raised to 60°C, the alkali solution was added, and the mixture was stirred at 55-60°C for 3h; the temperature was lowered to 20°C, and the mixture was filtered using a vacuum chromatography column while maintaining the nitrogen pressure at 0.2MPa; the mixture was dried at room temperature until no water droplets condensed on the column wall; the mixture was dried for 5h to obtain 10.48g of dry phenytoin sodium with a yield of 93.0%.

[0038] Example 3

[0039] See also Figure 1 , is the third embodiment of the present invention, which provides a method for preparing phenytoin sodium,

[0040] Put 25g of purified water, 50g of anhydrous ethanol, 25.97g of ferric chloride and 12.5g of benzoin into a 250ml reaction bottle, start stirring, heat to 40℃, keep at 40-60℃ for 6h, cool to 25℃, filter, and dry at 80℃ for 3h to obtain 13.23g of diphenylethylenedione with a yield of 96.8%.

[0041] Add 20 g of purified water and 5.3 g of sodium hydroxide into the reaction bottle, mix well, add 24 g of anhydrous ethanol, 3.7 g of urea, and 13 g of diphenylethylenedione, heat to 50°C, react at 70-80°C for 3 h, add 0.6 g of activated carbon, decolorize for 1 h, add 78 g of purified water and filter, cool the filtrate to 20°C, add dilute hydrochloric acid dropwise to adjust the pH value to 6.0; grow the crystal for 2 h, filter to obtain wet phenytoin, and dry at 70°C to obtain 14.5 g of dry phenytoin, with a yield of 98.5%.

[0042] 1.6g purified water and 1.6g sodium hydroxide were used to prepare alkali solution for later use; 100ml n-hexane and 10g phenytoin were added into the reaction bottle, the temperature was raised to 60°C, the alkali solution was added, and the mixture was stirred at 55-60°C for 3h; the temperature was lowered to 20°C and filtered using a vacuum chromatography column; the nitrogen pressure was maintained at 0.2MPa, and the mixture was dried at room temperature until no water droplets condensed on the column wall, and the drying was continued for 5h to obtain 9.98g of dry phenytoin sodium with a yield of 88.5%.

[0043] batch number Main peak (%) Impurity A Impurity B Impurity C Other impurities (%) Total impurities (%) Number of impurities 20240115 100.00 Not detected Not detected Not detected Not detected Not detected 0 20240120 100.00 Not detected Not detected Not detected Not detected Not detected 0 20240123 100.00 Not detected Not detected Not detected Not detected Not detected 0

[0044] The above is the detection data of phenytoin sodium obtained in the embodiment.

[0045] Related substance detection methods:

[0046] Related substances were determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512);

[0047] Solvent: 0.01 mol / L diammonium phosphate solution (pH adjusted to 2.0 with phosphoric acid)-acetonitrile-methanol (45:35:20);

[0048] Test solution Take the product, dissolve it in solvent and dilute it to make a solution containing about 1 mg per 1 ml;

[0049] Control solution: Accurately measure an appropriate amount of the test solution and quantitatively dilute it with solvent to make a solution containing about 1 μg per 1 ml;

[0050] System suitability solution Take appropriate amounts of phenytoin sodium reference substance, impurity A reference substance, impurity C reference substance, impurity D reference substance and impurity E reference substance, accurately weigh them, add solvent to dissolve and dilute to make a mixed solution containing about 1 mg of phenytoin sodium, 2 μg of impurity A, impurity C, impurity D and impurity E per 1 ml;

[0051] The chromatographic conditions were as follows: octadecylsilane bonded silica gel as filler (YMC-Pack ODS-AQ 4.6 mm × 250 mm 5 μm or a chromatographic column of equivalent performance); 0.01 mol / L ammonium dihydrogen phosphate solution (pH adjusted to 2.0 with phosphoric acid) as mobile phase A; acetonitrile as mobile phase B; gradient elution according to the table below; detection wavelength of 220 nm; flow rate of 1.0 ml per minute; column temperature of 25°C; injection volume of 20 μl.

[0052] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 80 20 40 20 80 50 20 80 53 80 20 63 80 20

[0053] System suitability requirements: In the system suitability solution chromatogram, the peak order is impurity C peak, impurity D peak, impurity E peak, phenytoin peak and impurity A peak; the separation between impurity D and impurity E peaks should be no less than 3.5.

[0054] Although the embodiments of the present invention have been shown and described, as detailed above, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing phenytoin sodium, characterized in that: The steps include: Synthesis of Phenytoin Sodium: Add benzoin and ferric chloride to the alcohol aqueous solution in sequence, stir and heat to reflux, cool and filter to obtain phenytoin sodium intermediate 1; The intermediate 1 is reacted with urea under alkaline conditions by reflux, purified water is added to filter and impurities are removed, and the filtrate is neutralized with hydrochloric acid and then crystallized and filtered to obtain phenytoin; Add phenytoin, sodium hydroxide, and a low boiling point solvent in sequence, heat up and reflux for reaction, cool to room temperature after the reaction is completed, filter, and dry to constant weight in a nitrogen-vacuum system at room temperature to obtain phenytoin sodium; The reaction equation is as follows:

2. A method for preparing phenytoin sodium according to claim 1, characterized in that: The molar ratio of the ferric chloride to benzoin is 1.0-2.0:

1.

3. A method for preparing phenytoin sodium according to claim 1, characterized in that: The molar ratio of the sodium hydroxide to the intermediate 1 is 1:1.0-1.

5.

4. A method for preparing phenytoin sodium according to claim 1, characterized in that: The molar ratio of the urea to the intermediate 1 is 1:1.0-1.

5.

5. A method for preparing phenytoin sodium according to claim 1, characterized in that: The amount of purified water used is 5 to 10 times the mass of the intermediate 1.

6. A method for preparing phenytoin sodium according to claim 1, characterized in that: The concentration of the hydrochloric acid used is 15% to 35%.

7. A method for preparing phenytoin sodium according to claim 1, characterized in that: The crystallization temperature is 10-40°C.

8. A method for preparing phenytoin sodium according to claim 1, characterized in that: The solvent is one or more of dichloromethane, n-hexane and acetone.

9. A method for preparing phenytoin sodium according to claim 1, characterized in that: The molar ratio of the sodium hydroxide to phenytoin is 1.0 to 1.

2.

10. A method for preparing phenytoin sodium according to claim 1, characterized in that: The reaction temperature is 40-90°C.

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