One-pot method for synthesizing phenytoin

Abstract

The invention discloses a method for synthesizing phenytoin in one pot, which specifically comprises the following steps: using benzoin as a raw material, adding an inorganic base in DMSO, and performing an oxidation reaction; after the oxidation reaction is completed, cooling the reaction solution to room temperature, adding sodium hydroxide and urea, and performing an ultrasonic cyclization reaction; after the reaction, adding water and filtering, adjusting the pH of the filtrate to acidic, precipitating white solid phenytoin, and filtering to obtain the product. The method of the invention is simple to operate, does not require additional separation and purification steps for the intermediate, has a fast reaction speed, a high reaction yield, uses DMSO as an oxidant and a solvent, has low environmental pollution, can effectively reduce the reaction cost, and is easy to promote and use.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, relates to a method for synthesizing phenytoin, and particularly relates to a method for synthesizing phenytoin by a one-pot method. Background Art

[0002] Phenytoin sodium is the first choice drug for the treatment of epilepsy. It is clinically used for the treatment of grand mal seizures, psychomotor seizures and arrhythmia. It can also be used to treat trigeminal neuralgia, latent dystrophic epidermolysis bullosa, paroxysmal choreoathetosis, paroxysmal control disorders, myotonia, and cardiac conduction disorders in the case of tricyclic antidepressant overdose. After years of clinical application, it has been proven to be one of the effective anti-epileptic drugs, especially for grand mal seizures.

[0003] At present, the main process route for the synthesis of phenytoin sodium includes four steps: preparing the intermediate benzoin by benzoin condensation reaction of benzaldehyde, benzoin oxidation to obtain benzil, condensation of benzil and urea in the presence of sodium hydroxide to obtain phenytoin, and salt formation. Among them, phenytoin is an important intermediate in the synthesis of phenytoin sodium, and its structure is as follows:

[0004]

[0005] Phenytoin and its derivatives are also important intermediates for the synthesis of some pharmaceutical and chemical products. It can synthesize fosphenytoin, etc. Using benzoin as the raw material, it is usually necessary to synthesize phenytoin in two steps. Benzoin is first oxidized under acidic conditions to obtain benzil, which is then separated, purified, and dried, and then cyclized with urea under alkaline conditions at high temperature to obtain phenytoin. The reaction solvent consumption is large, the environmental pollution is large, the operation is cumbersome, and the synthesis time is long.

[0006] Although there are literature reports on ultrasound-assisted cyclization reactions using alcohol as solvent, we found during the verification process that the product obtained was not phenytoin, but a condensation product of two molecules of urea and benzil. In addition, a large amount of the raw material benzil was recovered.

[0007]

[0008] Condensation by-products

[0009] Therefore, it is of great significance to explore simpler, safer, faster and more inexpensive chemical synthesis methods for synthesizing phenytoin and its derivatives. Summary of the invention

[0010] In view of the deficiencies in the prior art, the object of the present invention is to provide a one-pot method for synthesizing phenytoin. The method of the present invention is simple to operate, does not require additional separation and purification steps for intermediates, has a fast reaction speed, a high reaction yield, uses DMSO as an oxidant and a solvent, has low environmental pollution, can effectively reduce reaction costs, and is easy to promote and use.

[0011] The present invention is achieved through the following technical solutions:

[0012] The one-pot method for synthesizing phenytoin comprises the following steps:

[0013] Benzoin is used as a raw material, an inorganic base is added to DMSO, and an oxidation reaction is carried out; after the oxidation reaction is completed, the reaction solution is cooled to room temperature, sodium hydroxide and urea are added, and an ultrasonic cyclization reaction is carried out. After the reaction, water is added and filtered, and the pH of the filtrate is adjusted to acidic, white solid phenytoin is precipitated, and the product is obtained by filtering.

[0014] The chemical reaction equation is as follows:

[0015]

[0016] A further improvement of the present invention is:

[0017] The inorganic base is one or a mixture of two or more of potassium carbonate, sodium carbonate or cesium carbonate.

[0018] Furthermore, the temperature of the oxidation reaction is 0-130°C, and the time is 30min-120min.

[0019] Preferably, the oxidation reaction temperature is 90°C-125°C and the time is 1.5h.

[0020] Furthermore, the temperature of the cyclization reaction is 0-50°C and the time is 2-10 min.

[0021] Preferably, the cyclization reaction is carried out at a temperature of 10-25°C and a time of 5 minutes.

[0022] Furthermore, the molar ratio of benzoin, inorganic base, DMSO, sodium hydroxide and urea is 1:(0.4-0.6):(1-50):(3-5):(2-3).

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention adopts a one-pot reaction to avoid separation of the oxidation product benzil, has simple operation steps and high product yield;

[0025] The present invention uses DMSO as an oxidant and a solvent for the cyclization reaction, and the amount of solvent used is relatively small;

[0026] The cyclization reaction of the present invention uses ultrasound to assist, which has a short reaction time, a high yield and good product purity.

[0027] In summary, the method of the present invention is simple to operate, does not require additional separation and purification steps for the intermediates, has a fast reaction speed, a high reaction yield, uses DMSO as an oxidant and a solvent, has low environmental pollution, can effectively reduce the reaction cost, and is easy to promote and use. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of phenytoin prepared in Example 1;

[0029] Figure 2 The carbon-NMR spectrum of phenytoin prepared in Example 1 is shown in FIG. DETAILED DESCRIPTION

[0030] The present invention is described in detail below in conjunction with specific embodiments.

[0031] Example 1

[0032] Add 424 mg of benzoin, 138 mg of potassium carbonate, and 1 mL of DMSO to the reaction flask, and heat to 125 degrees Celsius for 90 min under magnetic stirring. After the reaction is completed, cool the reaction solution to room temperature, add 160 mg of urea and 240 mg of NaOH, stir evenly, and then react with ultrasonic assistance for 5 min. After the reaction is completed, add 30 mL of water to the reaction flask and filter. Collect the filtrate, add hydrochloric acid to adjust the pH to 2, and a large amount of white solid is generated. Filter and dry to obtain the target compound phenytoin 220 mg, with a yield of 43.7%. Mp 296-298. 1 H NMR (400MHz DMSO- d 6): δ H 11.10 (s, 1H); 9.31 (s, 1H); 7.32-7.42 (m, 10H). 13 C NMR (75MHz DMSO- d 6): δ C 174.81; 155.98; 139.92; 128.50; 128.02; 126.57; 70.20

[0033] Example 2

[0034] Add 424 mg of benzoin, 325 mg of cesium carbonate, and 0.6 mL of DMSO to the reaction flask, and heat to 125 degrees Celsius for 60 min under magnetic stirring. After the reaction is completed, cool the reaction solution to room temperature, add 160 mg of urea and 240 mg of NaOH, stir evenly, and then react with ultrasonic assistance for 5 min. After the reaction is completed, add 30 mL of water to the reaction flask and filter. Collect the filtrate, add hydrochloric acid to adjust the pH to 2, and a large amount of white solid is generated. Filter and dry to obtain 300 mg of the target compound phenytoin with a yield of 59.5%. Mp 297-299. TLC R f The value is consistent with the standard.

[0035] Example 3

[0036] Add 424 mg of benzoin, 106 mg of sodium carbonate, and 1 mL of DMSO to the reaction flask, heat to 125 degrees Celsius and react for 120 min under magnetic stirring. After the reaction is completed, cool the reaction solution to room temperature, add 160 mg of urea and 240 mg of NaOH, stir evenly, and then react with ultrasonic assistance for 5 min. After the reaction is completed, add 30 mL of water to the reaction flask and filter. Collect the filtrate, add hydrochloric acid to adjust the pH to 2, and a large amount of white solid is generated. Filter and dry to obtain the target compound phenytoin 200 mg, with a yield of 39.7%. Mp 295-298. TLC R f The value is consistent with the standard.

[0037] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. One-pot synthesis of phenytoin, It is characterized in that The following steps are involved: Benzoin is used as a raw material, an inorganic base is added to DMSO, and an oxidation reaction is carried out; after the oxidation reaction is completed, the reaction solution is cooled to room temperature, sodium hydroxide and urea are added, and an ultrasonic cyclization reaction is carried out. After the reaction, water is added and filtered, and the pH of the filtrate is adjusted to acidic, white solid phenytoin is precipitated, and the product is obtained by filtering; The inorganic base is cesium carbonate; The oxidation reaction temperature is 90°C-125°C and the time is 60-120min; The temperature of the cyclization reaction is 10-25°C and the time is 5 minutes; The molar ratio of benzoin, inorganic base, DMSO and sodium hydroxide is 1:(0.4-0.6):(1-50):(3-5).

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