Preparation method of fosphenytoin sodium

Abstract

The invention relates to a preparation method of fosphenytoin sodium, which is used for directly preparing fosphenytoin sodium from a compound 3-hydroxymethyl phenytoin shown as a formula I by a one-pot method, and comprises the following steps: 1) carrying out chlorination reaction on the compound shown as the formula I and a chlorination reagent to obtain a solution of a compound shown as a formula II; 2) in the presence of a catalyst a, adding a compound of formula III into the solution of the compound of formula II for reaction to obtain a compound of formula IV, and 3) performing catalytic hydrogenation reaction on the compound of formula IV, filtering, dropwise adding an inorganic alkali solution of sodium for salifying, cooling, crystallizing and filtering to obtain a compound of formula VI.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing fosphenytoin sodium. Background Art

[0002] Fosphenytoin Sodium, English name: Fosphenytoin Sodium, is a drug administered by intravenous drip or intramuscular injection. It is used to control the spasm symptoms of patients with primary epilepsy, prevent and treat convulsive seizures during neurosurgery, and avoid the disadvantage that epileptic patients cannot swallow medicines during an attack.

[0003] Fosphenytoin sodium structure: (VI) Most of the existing production processes of fosphenytoin sodium use phenytoin as the raw material, obtain 3-hydroxymethylphenytoin through hydroxymethylation, obtain 3-chloromethylphenytoin through chlorination reaction using phosphorus oxychloride, and then esterify with phosphate metal salt compounds to obtain 3-hydroxymethyl-phenytoin di-tert-butyl phosphate, and then hydrogenate and form salts to obtain fosphenytoin sodium.

[0004] Reference 1 (Jin Xueping et al., Chemistry and Bioengineering, 2007, 24 (12): 56-57) reported a method for preparing fosphenytoin sodium, which uses phenytoin as a raw material and undergoes hydroxymethylation, chlorination, esterification, hydrogenation, salt formation and other steps to obtain fosphenytoin sodium. The process route is as follows:

[0005] Although this route reduces the use of heavy metal silver compared to the previous silver salt method, the sulfur dioxide produced as a byproduct of thionyl chloride is extremely polluting to the environment, and the process may produce genotoxic impurities such as methane sulfonate, and there are problems such as low yield (total yield is 35.9%) and poor process controllability.

[0006] Document 2 (Chinese patent application number: CN201010104658.9) discloses a method for preparing a fosphenytoin sodium intermediate, using a compound of formula II (II) is used as the raw material, and condensed with dibenzyl phosphate silver salt in a toluene system. The reaction is completed after reflux reaction for 10 hours, the toluene is concentrated, and ethanol is added for crystallization. The yield is 60-62% and the content is 99.1%. However, the process has high temperature, long reaction time, and the dibenzyl phosphate silver used in the synthesis process is expensive, and the silver by-product is difficult to remove. In addition, the yield of this process is low, only about 60%.

[0007] Document 3 (patent publication number JP2018052859A) discloses a method for preparing fosphenytoin sodium, wherein phenytoin is used as a raw material and first hydroxylated with formaldehyde to obtain a compound of formula I (I), and then react with cuprous chloride to obtain a compound of formula II (II), a compound of formula II and a compound of formula III (III) condensed under potassium iodide catalysis to obtain a compound of formula IV (IV), the compound of formula IV is catalytically hydrogenated in a methanol system to obtain a compound of formula V (V) Re-salt crystallization to obtain the compound of formula VI (VI). The molar yield of 3-hydroxymethylphenytoin to fosphenytoin sodium in this route is only about 51%, heavy metal ions of copper are introduced, and the materials used, such as cuprous chloride and potassium iodide, are relatively expensive. Summary of the invention

[0008] The following is an overview of the subject matter described in detail herein. This overview is not intended to limit the scope of protection of this application.

[0009] The present application develops a preparation process for fosphenytoin sodium which is easy to operate, has low pollution, and has a yield and product purity comparable to or even higher than that of the prior art, successfully solving the problems existing in the prior art.

[0010] In one aspect, the present application provides a method for preparing fosphenytoin sodium, comprising the following steps: 1) subjecting the compound of formula I to a chlorination reaction with a chlorination agent to obtain a solution of the compound of formula II, wherein the structural formulas of the compound of formula I and the compound of formula II are as follows: I, II; 2) In the presence of catalyst a, adding a compound of formula III to a solution of a compound of formula II for reaction to obtain a compound of formula IV; wherein the structural formulas of the compound of formula III and the compound of formula IV are as follows: III, IV; 3) Catalytically hydrogenate the compound of formula IV, filter, dropwise add sodium inorganic base solution to form salt, cool and crystallize, filter, and obtain the compound of formula VI VI.

[0011] In an exemplary embodiment, the method directly prepares fosphenytoin sodium from the compound of formula I, 3-hydroxymethylphenytoin, in one pot.

[0012] In an exemplary embodiment, the chlorinating agent is oxalyl chloride.

[0013] In an exemplary embodiment, step 1) comprises: under alkaline conditions, adding the compound of formula I to solvent a and dropping a chlorination agent, stirring and heating to the reaction temperature, washing with water after the reaction is completed, and drying to obtain a solution of the compound of formula II.

[0014] In an exemplary embodiment, in step 1), the alkaline condition refers to the condition in which at least one of the following organic bases exists: triethylamine, pyridine, dimethylaminopyridine, 1,8-diazabicycloundec-7-ene (DBU), etc.; Preferably, it is triethylamine.

[0015] In an exemplary embodiment, in step 1), the solvent a is a water-insoluble organic solvent; Optionally, the solvent a is selected from at least one of the following: dichloromethane, chloroform, ethyl acetate, isopropyl acetate, toluene, and chlorobenzene; Toluene is preferred.

[0016] In an exemplary embodiment, in step 1), the compound of formula I reacts with a chlorinating agent in the presence of a catalytic amount of an organic base in a solvent a.

[0017] In an exemplary embodiment, in step 1), the mass ratio of the compound of formula I to the solvent a is 1:5-10, preferably 1:6-7.

[0018] In an exemplary embodiment, in step 1), the weight ratio of the compound of formula I to the organic base is 1:0.05-0.2, preferably 1:0.08-0.1.

[0019] In an exemplary embodiment, in step 1), the molar ratio of the compound of formula I to the chlorination agent is 1:1.1-2.0, preferably 1:1.2-1.3.

[0020] In an exemplary embodiment, in step 1), the reaction temperature of the compound of formula I and the chlorination agent is 5-30°C, for example, 15°C or 25°C.

[0021] In an exemplary embodiment, in step 1), the reaction time of the compound of formula I and the chlorination agent is 10-20 h, preferably 13-15 h, for example, 13 h.

[0022] In an exemplary embodiment, step 2) comprises: adding a compound of formula III and a catalyst a to a solution of a compound of formula II, stirring and heating to a reaction temperature to carry out a reaction; after the reaction is completed, filtering, washing with water, and concentrating to obtain a compound of formula IV.

[0023] In an exemplary embodiment, in step 2), in the compound of formula III, M is an alkali metal ion selected from potassium or sodium.

[0024] In an exemplary embodiment, in step 2), the compound of formula III is selected from at least one of dibenzyl phosphate sodium salt and dibenzyl phosphate potassium salt.

[0025] In an exemplary embodiment, in step 2), the catalyst a is selected from at least one of the following: pyridine, triethylamine, N,N-dimethylformamide, N,N-dimethylacetamide, 1,8-diazabicycloundec-7-ene; preferably N,N-dimethylformamide.

[0026] In an exemplary embodiment, in step 2), the weight ratio of the compound of formula II to catalyst a is 1:0.05-0.2, preferably 1:0.1-0.14.

[0027] In an exemplary embodiment, in step 2), the molar ratio of the compound of formula II to the compound of formula III is 1:0.8-1.2, preferably 1:0.95-1.05.

[0028] In an exemplary embodiment, in step 2), the reaction temperature of the compound of formula II and the compound of formula III is 40-100°C, preferably 80-90°C, for example 80°C.

[0029] In an exemplary embodiment, in step 2), the reaction time of the compound of formula II and the compound of formula III is 10-25 h, preferably 17-20 h, for example 17 h.

[0030] In an exemplary embodiment, step 3) comprises: adding the compound of formula IV to solvent b and heating until the solution is clear, adding palladium carbon and introducing hydrogen to carry out a hydrogenation reaction; after the reaction is completed, filtering, dropping an inorganic base of sodium to form a salt, cooling and crystallizing, and filtering.

[0031] In an exemplary embodiment, in step 3), the solvent b is selected from at least one of the following: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol; preferably ethanol.

[0032] In an exemplary embodiment, in step 3), the weight ratio of the compound of formula IV to the solvent b is 1:5-15, preferably 1:8-11.

[0033] In an exemplary embodiment, in step 3), the pressure of the reaction of the compound of formula IV with hydrogen is 0.005 MPa-0.05 MPa, preferably 0.02 MPa-0.03 MPa, for example, 0.02 MPa.

[0034] In an exemplary embodiment, in step 3), the palladium carbon is 5% palladium carbon or 10% palladium carbon.

[0035] In an exemplary embodiment, in step 3), the weight ratio of the compound of formula IV to palladium on carbon is 1:0.05-0.2; preferably, 1:0.1.

[0036] In an exemplary embodiment, in step 3), the temperature for reacting the compound of formula IV with hydrogen is 30°C-60°C, preferably 45-50°C, for example 50°C.

[0037] In an exemplary embodiment, in step 3), the reaction time of the compound of formula IV and hydrogen is 18-35 h, preferably 24-27 h, for example, 24 h.

[0038] In an exemplary embodiment, in step 3), the inorganic base of sodium is selected from at least one of the following: sodium carbonate, sodium bicarbonate and sodium hydroxide; preferably sodium hydroxide.

[0039] In an exemplary embodiment, in step 3), an inorganic base such as sodium is added to adjust the pH value of the system to 7-10, preferably 7.5-8.0.

[0040] In an exemplary embodiment, in step 3), the crystallization temperature is 0-15°C, preferably 0-5°C.

[0041] In an exemplary embodiment, the method comprises the following steps: 1) Preparation of 3-chloromethyl-phenytoin, a compound of formula II: 10.0 g of the compound of formula I was added to 60 g of toluene and stirred, and the temperature was lowered to 10°C. 1.0 g of triethylamine was added, and 5.4 g of oxalyl chloride was added dropwise at a temperature below 15°C. After the addition, the temperature was kept at 15°C for 13 hours. The reaction was stopped, 50 g of purified water was added, and the temperature was kept at 15°C for 30 minutes. The mixture was allowed to stand for separation, and the pH of the organic phase was adjusted to 7-8 with 5% sodium carbonate. The mixture was allowed to stand for separation, and anhydrous sodium sulfate was added to the organic phase to dry it to a moisture content of less than 0.5%. After drying, the mixture was filtered to obtain a toluene solution of the compound of formula II. 2) Preparation of 3-hydroxymethyl-phenytoin dibenzyl phosphate of formula IV compound: To the toluene solution of the compound of formula II obtained in step 1), 10.6 g of sodium dibenzyl phosphate and 1.1 g of N,N-dimethylformamide were added, the temperature was raised to 80° C. with stirring, and the reaction was kept warm for 17 hours. After the reaction was completed, 50 g of purified water was added to wash the toluene phase, and the toluene phase was concentrated until the flow was cut off to obtain an oily compound of formula IV; 3) Preparation of the compound of formula VI, fosphenytoin sodium: 160 g of ethanol was added to 20.1 g of the oily substance of the compound of formula IV, and the temperature was raised to 50° C. to dissolve, and 2 g of 10% palladium carbon was added, and hydrogen was introduced to maintain 0.02 MPa for 24 hours. After the reaction was completed, it was filtered, and a 10% sodium hydroxide solution was added dropwise to adjust the pH to 7.5-8, and the temperature was lowered to 5° C. for crystallization for 2 hours, and 13.6 g of the wet product was filtered, and the water content was reduced to less than 0.5% to obtain a dry product of the compound of formula VI.

[0042] In an exemplary embodiment, the method comprises the following steps: 1) Preparation of 3-chloromethyl-phenytoin, a compound of formula II: Add 10.0g of the compound of formula I to 60g of toluene and stir, cool to 10°C, add 1.0g of triethylamine, control the temperature below 15°C, add 5.4g of oxalyl chloride dropwise, keep the temperature at 25°C and react for 13h. Stop the reaction, add 50g of purified water, control the temperature at 15°C and stir for 30 minutes, let stand and separate, adjust the pH of the organic phase to 6-7 with 5% sodium carbonate, let stand and separate, add anhydrous sodium sulfate to dry the organic phase to less than 0.5% water content, filter after drying to obtain a toluene solution of the compound of formula II;

[0043] 2) Preparation of 3-hydroxymethyl-phenytoin dibenzyl phosphate of formula IV compound: To the toluene solution of the compound of formula II obtained in step 1), 10.6 g of sodium dibenzyl phosphate and 1.1 g of triethylamine were added, the mixture was stirred and heated to 80° C., and the mixture was kept warm for 17 hours. After the reaction, 50 g of purified water was added to wash the toluene phase, and the toluene phase was concentrated until the flow was cut off to obtain an oily compound of formula IV; 3) Preparation of the compound of formula VI, fosphenytoin sodium: 160 g of ethanol was added to 19.9 g of the oily substance of the compound of formula IV, and the temperature was raised to 50° C. to dissolve, and 2 g of 10% palladium carbon was added, and hydrogen was introduced to maintain 0.02 MPa for reaction for 24 h. After the reaction was completed, the mixture was filtered, and a 10% sodium hydroxide solution was added dropwise to adjust the pH to 7.5-8. The mixture was cooled to 5° C. and crystallized for 2 hours. 13.6 g of the wet product was filtered, and the dry product of the compound of formula VI was obtained by drying under reduced pressure to a moisture content of less than 0.5%.

[0044] In an exemplary embodiment, the method comprises the following steps: 1) Preparation of 3-chloromethyl-phenytoin, a compound of formula II: 10.0 g of the compound of formula I was added to 60 g of toluene and stirred, and the temperature was lowered to 10°C. 1.0 g of triethylamine was added, and 5.4 g of oxalyl chloride was added dropwise at a temperature below 15°C. After the addition, the temperature was kept at 15°C for 13 hours. The reaction was stopped, 50 g of purified water was added, and the temperature was kept at 15°C for 30 minutes. The mixture was allowed to stand for separation, and the pH of the organic phase was adjusted to 7-8 with 5% sodium carbonate. The mixture was allowed to stand for separation, and anhydrous sodium sulfate was added to the organic phase to dry it to a moisture content of less than 0.5%. After drying, the mixture was filtered to obtain a toluene solution of the compound of formula II. 2) Preparation of 3-hydroxymethyl-phenytoin dibenzyl phosphate of formula IV compound: To the toluene solution of the compound of formula II obtained in step 1), 11.2 g of potassium dibenzyl phosphate and 1.1 g of N,N-dimethylformamide were added, the temperature was raised to 80° C. with stirring, and the reaction was kept warm for 17 hours. After the reaction was completed, 50 g of purified water was added to wash the toluene phase, and the toluene phase was concentrated until the flow was cut off to obtain an oily compound of formula IV; 3) Preparation of the compound of formula VI, fosphenytoin sodium: 160 g of methanol was added to 20.1 g of the oily substance of the compound of formula IV, and the temperature was raised to 50° C. to dissolve, 2 g of 10% palladium carbon was added, and hydrogen was introduced to maintain 0.02 MPa for reaction for 24 h. After the reaction was completed, the mixture was filtered, and a 10% sodium hydroxide solution was added dropwise to adjust the pH to 7.5-8. The mixture was cooled to 5° C. and crystallized for 2 hours. 13.6 g of the wet product was filtered, and the moisture content was reduced to less than 0.5% to obtain a dry product of the compound of formula VI.

[0045] Compared with the existing related technologies, this application has the following technical effects: (1) When preparing the compound of formula II, oxalyl chloride is used instead of highly polluting reagents such as phosphorus oxychloride and thionyl chloride, which results in no highly polluting by-products and is easy to handle; (2) When preparing the compound of formula IV, an organic catalyst such as DMF or triethylamine is used instead of potassium iodide or sodium iodide as a catalyst, thereby avoiding the use of expensive reagents such as potassium iodide or sodium iodide and reducing costs; (3) Fosphenytoin sodium can be directly prepared from the compound of formula I in one pot, so that the production efficiency of the method of the present application is comparable to or even higher than that of the prior art.

[0046] Therefore, the method of the present application directly prepares fosphenytoin sodium from 3-hydroxymethylphenytoin in one pot, and the process operation involved is simple, low-pollution, and the yield is equivalent to or even higher than the prior art; oxalyl chloride is used in the chlorination reaction to replace the highly polluting chlorination reagents such as phosphorus oxychloride and thionyl chloride that are currently used in production. Organic catalysts such as triethylamine and DMF are added to the condensation reaction to replace expensive catalysts such as potassium iodide and sodium iodide. The direct preparation of fosphenytoin sodium from 3-hydroxy compounds avoids the removal of intermediates, which greatly improves production efficiency in production.

[0047] Other features and advantages of the present application will be described in the following description, and partly become apparent from the description, or be understood by implementing the present application. Other advantages of the present application can be realized and obtained by the schemes described in the description. DETAILED DESCRIPTION

[0048] In order to make the purpose, technical solution and advantages of the present application more clear, the embodiments of the present application will be described in detail below. It should be noted that the embodiments and features in the embodiments of the present application can be combined with each other arbitrarily without conflict.

[0049] The present invention is further described in detail below in conjunction with specific examples, but the examples should not be construed as limiting the present invention. The raw materials of this application are all conventional products on the market.

[0050] The determination method of fosphenytoin sodium is USP39, pages 4051-4052.

[0051] Among them, the source of the compound represented by formula I of the present application (3-hydroxymethyl-phenytoin) is not particularly limited and can be generally commercially available; the source of the compound represented by formula III is not particularly limited and can be generally commercially available.

[0052] Example 1 (1) Preparation of 3-chloromethyl-phenytoin, a compound of formula II: 10.0g (35.4mmol) of the compound of formula I was added to 60g of toluene and stirred, cooled to 10°C, 1.0g of triethylamine was added, 5.4g (42.5mmol) of oxalyl chloride was added dropwise at a temperature below 15°C, and the temperature was kept at 15°C for 13h. The reaction was stopped, 50g of purified water was added, the temperature was kept at 15°C and stirred for 30 minutes, and the mixture was allowed to stand for separation. The organic phase was adjusted to pH 7-8 with 5% sodium carbonate, and the mixture was allowed to stand for separation. Anhydrous sodium sulfate was added to the organic phase to dry it to a moisture content of less than 0.5%, and filtered after drying to obtain a toluene solution of the compound of formula II.

[0053] (2) Preparation of 3-hydroxymethyl-phenytoin dibenzyl phosphate of formula IV: To the toluene solution of the compound of formula II obtained in step (1), 10.6 g (35.4 mmol) of sodium dibenzyl phosphate and 1.1 g of N,N-dimethylformamide were added, the temperature was raised to 80°C with stirring, and the reaction was kept warm for 17 hours. After the reaction was completed, 50 g of purified water was added to wash the toluene phase, and the toluene phase was concentrated to constant weight to obtain 20.1 g of an oily compound of formula IV with a purity of 90.4%, a content of 85.8%, and a pure molar yield of 89.8%.

[0054] (3) Preparation of the compound of formula VI, fosphenytoin sodium: Add 160g of ethanol to 20.1g of the oily compound of formula IV and heat it to 50°C to dissolve it. Add 2g of 10% palladium carbon, pass hydrogen and keep the reaction at 0.02MPa for 24h. After the reaction is completed, filter, drip 10% sodium hydroxide solution to adjust the pH to 7.5-8, cool to 5°C for crystallization for 2 hours, filter to obtain 13.6g of wet product, and dry under reduced pressure to less than 0.5% of moisture to obtain 11.6g of dry product of formula VI, with a molar yield of 72.0% and a purity of 99.4%.

[0055] Example 2 (1) Preparation of the compound 3-chloromethyl-phenytoin represented by formula II: 10.0g (35.4mmol) of the compound represented by formula I was added to 60g of toluene and stirred, cooled to 10°C, 1.0g of triethylamine was added, 5.4g (42.5mmol) of oxalyl chloride was added dropwise at a temperature below 15°C, and the temperature was kept at 25°C for 13h. The reaction was stopped, 50g of purified water was added, the temperature was controlled at 15°C and stirred for 30 minutes, and the mixture was allowed to stand for separation. The organic phase was adjusted to a pH of 6-7 with 5% sodium carbonate, and the mixture was allowed to stand for separation. Anhydrous sodium sulfate was added to the organic phase to dry it to a moisture content of less than 0.5%, and filtered after drying to obtain a toluene solution of formula II.

[0056] (2) Preparation of the compound 3-hydroxymethyl-phenytoin dibenzyl phosphate represented by formula IV: To the toluene solution of formula II obtained in step (1), 10.6 g (35.4 mmol) of sodium dibenzyl phosphate and 1.1 g of triethylamine were added, the mixture was stirred and heated to 80°C, and the reaction was kept warm for 17 hours. After the reaction was completed, 50 g of purified water was added to wash the toluene phase, and the toluene phase was concentrated to constant weight to obtain 19.9 g of an oily substance of formula IV with a purity of 88.2%, a content of 83.9%, and a pure molar yield of 86.9%.

[0057] (3) Preparation of the compound fosphenytoin sodium represented by formula VI: Add 160g of ethanol to 19.9g of the oily substance of Formula IV and heat it to 50°C to dissolve it, add 2g of 10% palladium carbon, pass hydrogen and keep the reaction at 0.02MPa for 24h. After the reaction is completed, filter, drip 10% sodium hydroxide solution to adjust the pH to 7.5-8, cool to 5°C for crystallization for 2 hours, filter to obtain 13.4g of wet product, and dry it under reduced pressure to less than 0.5% of water to obtain 11.3g of dry product of Formula VI, with a molar yield of 70.2% and a purity of 99.2%.

[0058] Example 3 (1) Preparation of 3-chloromethyl-phenytoin, a compound of formula II: 10.0g (35.4mmol) of the compound represented by formula I was added to 60g of toluene and stirred, cooled to 10°C, 1.0g of triethylamine was added, 5.4g (42.5mmol) of oxalyl chloride was added dropwise at a temperature below 15°C, and the temperature was kept at 15°C for 13h. The reaction was stopped, 50g of purified water was added, the temperature was kept at 15°C and stirred for 30 minutes, and the mixture was allowed to stand for separation. The organic phase was adjusted to a pH of 7-8 with 5% sodium carbonate, and the mixture was allowed to stand for separation. Anhydrous sodium sulfate was added to the organic phase to dry it to a moisture content of less than 0.5%, and filtered after drying to obtain a toluene solution of formula II.

[0059] (2) Preparation of the compound 3-hydroxymethyl-phenytoin dibenzyl phosphate represented by formula IV: To the toluene solution of formula II obtained in step (1), 11.2 g (35.4 mmol) of potassium dibenzyl phosphate and 1.1 g of N,N-dimethylformamide were added, the mixture was stirred and heated to 80°C, and the reaction was kept warm for 17 hours. After the reaction, 50 g of purified water was added to wash the toluene phase, and the toluene phase was concentrated to constant weight to obtain 20.1 g of an oily substance of formula IV with a purity of 90.5%, a content of 85.9%, and a pure molar yield of 89.9%.

[0060] (3) Preparation of the compound of formula VI, fosphenytoin sodium: Add 160g of methanol to 20.1g of the oily substance of Formula IV and heat it to 50°C to dissolve it. Add 2g of 10% palladium carbon, introduce hydrogen and keep the reaction at 0.02MPa for 24h. After the reaction is completed, filter, drip 10% sodium hydroxide solution to adjust the pH to 7.5-8, cool to 5°C for crystallization for 2 hours, filter to obtain 13.5g of wet product, and dry it under reduced pressure to less than 0.5% of water to obtain 11.5g of dry product of Formula VI, with a molar yield of 71.4% and a purity of 99.4%.

[0061] Comparative Example 1 (1) Preparation of 3-chloromethyl-phenytoin, a compound of formula II: 10.0g (35.4mmol) of the compound represented by formula I was added to 60g of toluene and stirred, cooled to 10°C, 1.0g of triethylamine was added, 5.4g (42.5mmol) of phosphorus oxychloride was added dropwise at a temperature below 15°C, and the temperature was kept at 15°C for 13h. The reaction was stopped, 50g of purified water was added, the temperature was controlled at 15°C and stirred for 30 minutes, and the mixture was allowed to stand for separation. The organic phase was adjusted to a pH of 7-8 with 5% sodium carbonate, and the mixture was allowed to stand for separation. Anhydrous sodium sulfate was added to the organic phase and dried to a moisture content of less than 0.5%. After drying, the mixture was filtered to obtain a toluene solution of formula II.

[0062] (2) Preparation of the compound 3-hydroxymethyl-phenytoin dibenzyl phosphate represented by formula IV: To the toluene solution of formula II obtained in step (1), 10.6 g (35.4 mmol) of sodium dibenzyl phosphate and 1.1 g of N,N-dimethylformamide were added, the mixture was stirred and heated to 80°C, and the reaction was kept warm for 17 hours. After the reaction, 50 g of purified water was added to wash the toluene phase, and the toluene phase was concentrated to constant weight to obtain 19.8 g of an oily substance of formula IV with a purity of 85.9%, a content of 84.9%, and a pure molar yield of 87.5%.

[0063] (3) Preparation of the compound fosphenytoin sodium represented by formula VI: Add 160g of ethanol to 19.8g of the oily compound of Formula IV and heat it to 50°C to dissolve it. Add 2g of 10% palladium carbon, introduce hydrogen and keep the reaction at 0.02MPa for 24h. After the reaction is completed, filter, drip 10% sodium hydroxide solution to adjust the pH to 7.5-8, cool to 5°C for crystallization for 2 hours, filter to obtain 13.4g of wet product, and dry under reduced pressure to less than 0.5% of water to obtain 11.4g of dry product of Formula VI, with a molar yield of 70.8% and a purity of 99.3%.

[0064] Comparative Example 2 (1) Preparation of Formula IV Compound 3-Hydroxymethyl-phenytoin Dibenzyl Phosphate To 10.6 g (35.4 mmol) of compound II, add 12.3 g (38.9 mmol) of potassium dibenzyl phosphate, 0.04 g of potassium iodide and 68 mL of acetonitrile, stir and heat to 60 ° C, keep warm for 4 hours, stop heating, add 68 ml of water, stir and cool to 5 ° C, keep warm for 2 hours to crystallize. Filter and dry the filter cake to obtain 17.0 g of solid with a purity of 99.3% and a yield of 88.5%.

[0065] (2) Preparation of the compound of formula VI, fosphenytoin sodium: Add 160g of ethanol to 17.0g of the solid compound of formula IV and heat it to 50°C to dissolve it. Add 2g of 10% palladium carbon, pass hydrogen and keep the reaction at 0.02MPa for 24h. After the reaction is completed, filter, drip 10% sodium hydroxide solution to adjust the pH to 7.5-8, cool to 5°C for crystallization for 2 hours, filter to obtain 13.6g of wet product, and dry under reduced pressure to less than 0.5% of moisture to obtain 11.5g of dry product of formula VI compound, with a total molar yield of 71.4% and a purity of 99.5%.

[0066] Comparative Example 3 (1) Preparation of 3-hydroxymethyl-phenytoin dibenzyl phosphate of formula IV: To a toluene solution of 9.8 g (32.6 mmol) of the compound of formula II, 10.6 g (35.4 mmol) of sodium dibenzyl phosphate and 0.03 g of sodium iodide were added, the temperature was raised to 60 ° C with stirring, and the reaction was kept warm for 20 hours. After the reaction, 50 g of purified water was added to wash the toluene phase, and the toluene phase was concentrated to constant weight to obtain 19.3 g of an oily compound of formula IV with a purity of 90.1%, a content of 83.4%, and a pure molar yield of 83.8%.

[0067] (2) Preparation of the compound of formula VI, fosphenytoin sodium: Add 160g of ethanol to 19.3g of the oily compound of formula IV and heat it to 50°C to dissolve it. Add 2g of 10% palladium carbon and introduce hydrogen to maintain 0.02MPa for 24h. After the reaction is completed, filter it, drop 10% sodium hydroxide solution to adjust the pH to 7.5-8, cool it to 5°C for crystallization for 2 hours, filter it to obtain 12.7g of wet product, and dry it under reduced pressure to less than 0.5% of moisture to obtain 10.9g of dry product of formula VI, with a molar yield of 67.6% and a purity of 99.3%.

[0068] Conclusion: The method of the present application directly prepares fosphenytoin sodium from 3-hydroxymethylphenytoin in one pot, and the process operation involved is simple, low-pollution, and the yield is equivalent to or even higher than that of the prior art; oxalyl chloride is used in the chlorination reaction to replace highly polluting chlorination reagents such as phosphorus oxychloride and thionyl chloride that are currently used in production. Organic catalysts such as triethylamine and DMF are added to the condensation reaction to replace expensive catalysts such as potassium iodide and sodium iodide. The direct preparation of fosphenytoin sodium from 3-hydroxy avoids the removal of intermediates, which greatly improves production efficiency in production.

[0069] Although the embodiments of the present application have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations on the present application. Ordinary technicians in this field can change, modify, replace and modify the above embodiments within the scope of the present application.

Claims

1. A method for preparing fosphenytoin sodium, characterized in that: The method directly prepares fosphenytoin sodium from the compound 3-hydroxymethylphenytoin of formula I in a one-pot process, comprising the following steps: 1) subjecting the compound of formula I to a chlorination reaction with a chlorination agent to obtain a solution of the compound of formula II, wherein the structural formulas of the compound of formula I and the compound of formula II are as follows: AND, II; 2) In the presence of catalyst a, adding a compound of formula III to a solution of the compound of formula II for reaction to obtain a compound of formula IV; wherein the structural formulas of the compound of formula III and the compound of formula IV are as follows: III, IV: 3) subjecting the compound of formula IV to catalytic hydrogenation reaction, filtering, dropping sodium inorganic base solution to form salt, cooling and crystallizing, filtering, and obtaining the compound of formula VI WE; Wherein, the chlorination reagent is oxalyl chloride; In the compound of formula III, M is an alkali metal ion selected from potassium or sodium; The catalyst a is selected from at least one of the following: pyridine, triethylamine, N,N-dimethylformamide, N,N-dimethylacetamide, and 1,8-diazabicycloundec-7-ene.

2. The method according to claim 1, characterized in that: Step 1) comprises: under alkaline conditions, adding the compound of formula I into solvent a and dropping the chlorination reagent, stirring and heating to the reaction temperature, washing with water after the reaction is completed, and drying to obtain a solution of the compound of formula II; The alkaline conditions refer to the presence of at least one of the following organic bases: triethylamine, pyridine, dimethylaminopyridine, 1,8-diazabicycloundec-7-ene; The solvent a is a water-insoluble organic solvent; optionally, the solvent a is selected from at least one of the following: dichloromethane, chloroform, ethyl acetate, isopropyl acetate, toluene, and chlorobenzene.

3. The method according to claim 2, characterized in that In step 1), the organic base is triethylamine; and / or The solvent a is toluene.

4. The method according to any one of claims 2 to 3, characterized in that In step 1), the mass ratio of the compound of formula I to the solvent a is 1:5-10; and / or The weight ratio of the compound of formula I to the organic base is 1:0.05-0.2; and / or The molar ratio of the compound of formula I to the chlorination agent is 1:1.1-2.0; and / or The reaction temperature of the compound of formula I and the chlorination agent is 5-30° C.; and / or The reaction time of the compound of formula I and the chlorination agent is 10-20 hours.

5. The method according to any one of claims 1 to 3, characterized in that Step 2) comprises: adding the compound of formula III and the catalyst a to the solution of the compound of formula II, stirring and heating to the reaction temperature to carry out the reaction; after the reaction is completed, filtering, washing with water, and concentrating to obtain the compound of formula IV.

6. The method according to any one of claims 1 to 3, characterized in that The catalyst a is N,N-dimethylformamide.

7. The method according to any one of claims 1 to 3, characterized in that In step 2), the weight ratio of the compound of formula II to catalyst a is 1:0.05-0.2; and / or The molar ratio of the compound of formula II to the compound of formula III is 1:0.8-1.2; and / or The reaction temperature of the compound of formula II and the compound of formula III is 40-100° C.; and / or The reaction time of the compound of formula II and the compound of formula III is 10-25 hours.

8. The method according to any one of claims 1 to 3, characterized in that Step 3) comprises: adding the compound of formula IV to solvent b and heating until the solution is clear, adding palladium carbon, and introducing hydrogen to carry out hydrogenation reaction; after the reaction is completed, filtering, dropping sodium inorganic base to form salt, cooling and crystallizing, and filtering; Wherein, the solvent b is selected from at least one of the following: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol.

9. The method according to claim 8, characterized in that In step 3), the inorganic base of sodium is selected from at least one of the following: sodium carbonate, sodium bicarbonate and sodium hydroxide.

10. The method according to claim 8, characterized in that In step 3), the weight ratio of the compound of formula IV to the solvent b is 1:5-15; and / or The pressure of the reaction of the compound of formula IV with hydrogen is 0.005MPa-0.05MPa; and / or The palladium carbon is 5% palladium carbon or 10% palladium carbon; and / or The weight ratio of the compound of formula IV to palladium on carbon is 1:0.05-0.2; and / or The temperature of the reaction of the compound of formula IV with hydrogen is 30°C-60°C; and / or The reaction time of the compound of formula IV and hydrogen is 18-35h; and / or Adding an inorganic base such as sodium to adjust the pH of the system to 7-10; and / or The crystallization temperature is 0-15°C.

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